Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed June 24, 2024.
Amendments
Applicant's amendment(s), filed June 24, 2024, is acknowledged. Applicant has cancelled Claims 9, 11, 15-17, 19-20, 24-29, 32-34, and 36-47, and amended Claims 1, 12, 18, 21-23, and 30-31.
Claims 1-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are pending and under consideration.
Priority
This application is a continuation of application 16/613,907 filed November 15, 2019, now U.S. Patent 11,958,887, which is a 371 of PCT/US2018/033247 filed on May 17, 2018. Applicant’s claim for the benefit of a prior-filed application provisional application 62/507,358 filed on May 17, 2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on June 24, 2024 that has been considered.
The information disclosure statement filed September 12, 2022 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
A plurality of NPL citation(s) have been lined through for being defective for one or more of these requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
1. Claim 8 and the Specification are objected to for the following reason: this application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because sequences are set forth in the specification that lack sequence identifiers.
Applicant a priori iterates the deficiencies of parent application 16/613,907.
See Office Action mailed October 3, 2022 in parent application 16/613,907.
Claim 8 recites the amino acid sequence SGGG without its corresponding SEQ ID NO.
The specification discloses the amino acid sequence SGGG (e.g. pg 2, line 11; pg 9, lines 10 and 21) without its corresponding SEQ ID NO.
Each nucleotide and/or amino acid sequence that meets the minimum length threshold must have its SEQ ID NO: in parenthesis next to each occurrence, i.e. SGGGSGGGSGGGSGGG (SEQ ID NO:4) (pg 2, line 12).
Applicants are required to comply with all of the requirements of 37 CFR 1.821 - 1.825. Any response to this office action that fails to meet all of these requirements will be considered non-responsive.
See U.S. Patent 11,958,887 claim 1, for example.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claims 1-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
Claim 1 recites the term “condensed tuberin (cTuberin)”.
As a second matter, the term “condensed” is relative terminology, and the claim fails to recite the reference Tuberin polypeptide from which “condensed” is to be determined.
The specification discloses “the disclosed methods for correcting mutations in TSC2 utilizes a condensed form of human tuberin, cTuberin” (pg 6, lines 32-33).
However, the instant claims are broader in scope to human Tuberin nucleic acid and amino acid sequences, e.g. as much as 10% divergence from human Tuberin (Claims 2, 4, and 10).
Inoki et al (Nature Cell Biology 4: 648-657, 2002; of record in parent application 16/613,907) taught rat TSC2 which is at least 91% identical to SEQ ID NO:10 (human TSC2).
See also SCORE search results of SEQ ID NO:10 clearly identifying non-human TSC2 proteins having as little as 96% to 99.6% identity to SEQ ID NO:10.
Furthermore, Inoki et al taught the rat TSC2, e.g. short and long forms, comprising a mutation at the Akt phosphorylation site T1462.
The rat TSC2 does not naturally comprise (syn. lacks) amino acids 451-1514 of human tuberin (SEQ ID NO:10). See sequence alignment in parent application 16/613,907 (Office Action mailed October 3, 2022).
Naturally occurring TSC2 short forms are necessarily “condensed” relative to their naturally-occurring long form counterparts.
The specification fails to disclose what specific amino acids are required to be present that objectively distinguishes a human cTuberin from a non-human cTuberin.
As a second matter, it is unclear if “cTuberin” is to be interpreted as a special definition. The specification discloses “cTuberin lacks amino acids 451-1514 of human tuberin” (pg 2, line 8). See also Figure 2A.
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The instant claims are structurally discordant with the potential special definition. The instant claims remain broader in scope to human Tuberin nucleic acid and amino acid sequences, reasonably encompassing TSC2 proteins naturally expressed in non-human species such as sea lion and non-human primates. The specification fails to disclose what specific amino acids are required to be present that objectively distinguishes a human cTuberin from a non-human cTuberin. The recited structural limitations are broader in scope than SEQ ID NO:1, a “cTuberin lacks amino acids 451-1514 of human tuberin” (pg 2, line 8).
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
3. Claims 31, 35, and 48 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The Examiner acknowledges that the instant 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection should have been made in the prosecution of parent application 16/613,907, now U.S. Patent 11,958,887, to wit, ‘887 claims 15-17 and 19-21.
Claim 31 recites a method of treating a patient having tuberous sclerosis complex (TSC), the method comprising the step of administering to said patient an engineered cTuberin comprising:
a) a hamartin binding region;
b) a GTPase-activating protein (GAP) region; and
c) lacking an Akt phosphorylation site Thr 1462.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the structure(s)/function(s) of condensed tuberin (cTuberin) [parameter 2];
the structure of the cTuberin pharmaceutical composition [parameter 3];
the dosage administered [parameter 4];
the administration route [parameter 5];
the disease/disorder/condition to be treated [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount (syn. subtherapeutic) to necessarily and predictably achieve a real-world, clinically meaningful treatment of a patient having tuberous sclerosis complex disease/disorder/condition.
Parameter 1
The specification discloses that “subject” and “patient” are interchangeable (e.g. pg 5, line 39). The specification discloses working examples by which non-human subjects, to wit, mice, are treated (e.g. Examples 5 and 11). The specification fails to disclose that “patient” is only limited to humans. Thus, the term “patient” is considered to read upon both human and non-human animals.
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claims are broad for encompassing an enormously vast genus of structurally and functionally undisclosed cTuberin polypeptides.
The specification discloses (e.g. pg 1, line 38), and Claim 10 recites, wherein the cTuberin has an amino acid sequence that is at least 90% identical to SEQ ID NO:1, which is 1807 amino acids in length.
Thus, the claims reasonably encompass as many as 181 amino acid substitutions, insertions, or deletions (90% identity).
20^181 = about 3x10^235 possible variants of a Tuberin polypeptide having at least 90% sequence identity to SEQ ID NO:10.
(calculator.net/exponent-calculator.html; last visited March 27, 2025)
Claim 2 recites wherein the cTuberin hamartin binding region has an amino acid sequence that is at least 90% identical to SEQ ID NO:2, which is 450 amino acids in length.
Thus, the claims reasonably encompass as many as 45 amino acid substitutions, insertions, or deletions (90% identity).
20^45 = about 3x10^58 possible variants of a Tuberin hamartin binding region having at least 90% sequence identity to SEQ ID NO:2.
Claim 4 recites wherein the cTuberin GTPase-activating protein (GAP) region has an amino acid sequence that is at least 90% identical to SEQ ID NO:3, which is 292 amino acids in length.
Thus, the claims reasonably encompass as many as 29 amino acid substitutions, insertions, or deletions (90% identity).
20^29 = about 5x10^37 possible variants of a Tuberin GTPase-activating protein (GAP) region having at least 90% sequence identity to SEQ ID NO:10.
Thus, the claims reasonably encompass an enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants.
Parameter 3
The claims are broad for reciting at a high level of generality a multitude of cTuberin pharmaceutical formularies, including, but not limited to, naked proteins and nucleic acid molecules such as plasmids, bacterial artificial chromosomes, cosmids, naked DNA, mRNA, phage vectors, viral vectors.
The specification discloses the use of rAAV9 viruses whose genomes encode the cTuberin polypeptide (e.g. Examples 5 and 11).
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 4
The claims are broad for failing to recite the dosage of the cTuberin protein pharmaceutical, nor cTuberin nucleic acid pharmaceutical, that is/are to be administered to the human and non-human subject/patient.
The specification is silent to cTuberin protein pharmaceutical dosages.
The claimed methods are broad for encompassing an rAAV vector dosage that is to be administered, including, but not limited to, as little as 1x10^1 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 5
The claims are broad for reciting at a high level of generality a multitude of anatomically distinct routes, by which the cTuberin protein pharmaceutical or cTuberin nucleic acid pharmaceutical is to be administered to the human and non-human subject/patient, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Parameter 6
The claims are directed to treating tuberous sclerosis complex (TSC) diseases/disorders/conditions. The specification discloses TSC presents as enlargement and increased proliferation of cells, forming tumors affecting the brain, heart, kidneys, skin, and lungs, or causing developmental delay, autism, epilepsy, and hydrocephaly (e.g. pg 1, lines 21-26).
Parameter 7
The claims are broad for reciting “treating” at a high level of generality.
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question:
A therapeutically effective amount to do what?
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount (syn. subtherapeutic) to necessarily and predictably achieve a real-world, clinically meaningful treatment of a patient having tuberous sclerosis complex disease/disorder/condition.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin protein variant pharmaceuticals or cTuberin nucleic acid pharmaceuticals must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses that “treating” refers to a therapeutic treatment for a condition, including reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results (e.g. pg 6, lines 1-17), or prevent the progression of disease, prevent spread of damage to uninjured cells (e.g. pg 20, lines 14-15), prevent the mutations or defects (e.g. pg 20, line28).
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025).
If there are multiple ways to measure “therapeutically effective dose”, to wit, cTuberin protein structure/function, dosage, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the cTuberin is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
4. Claim(s) 1-2, 4, 6-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Examiner acknowledges that the instant 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection should have been made in the prosecution of parent application 16/613,907, now U.S. Patent 11,958,887, to wit, ‘887 claims 1, 5, 7-13, 15-17, and 19-21.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Claim 1 recites an engineered cTuberin polypeptide comprising:
a) a hamartin binding region;
b) a GTPase-activating protein (GAP) region; and
c) lacking an Akt phosphorylation site Thr 1462.
Claim 31 recites a method of treating a patient having tuberous sclerosis complex (TSC), the method comprising the step of administering to said patient an engineered cTuberin comprising:
a) a hamartin binding region;
b) a GTPase-activating protein (GAP) region; and
c) lacking an Akt phosphorylation site Thr 1462.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
It is understood that in order to meaningfully treat the subject/patient, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the cTuberin pharmaceutical must be administered to the human and non-human subject/patient, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the structure(s)/function(s) of condensed tuberin (cTuberin) [parameter 2];
the structure of the cTuberin pharmaceutical composition [parameter 3];
the dosage administered [parameter 4];
the administration route [parameter 5];
the disease/disorder/condition to be treated [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount (syn. subtherapeutic) to necessarily and predictably achieve a real-world, clinically meaningful treatment of a patient having tuberous sclerosis complex disease/disorder/condition.
Parameter 1
The claims are broad for encompassing about 1x10^6 human and non-human animal species.
Parameter 2
The claims are broad for encompassing an enormously vast genus of structurally and functionally undisclosed cTuberin polypeptides.
The specification discloses (e.g. pg 1, line 38), and Claim 10 recites, wherein the cTuberin has an amino acid sequence that is at least 90% identical to SEQ ID NO:1, which is 1807 amino acids in length.
The claims reasonably encompass as many as 3x10^235, 3x10^58, and/or 5x10^37 possible cTuberin polypeptide variants.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity, that upon administration to the enormous genus of human and non-human animals will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, enormously vast genus of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity, that upon administration to the enormous genus of human and non-human animals will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Parameter 3
The claims are broad for reciting at a high level of generality a multitude of cTuberin pharmaceutical formularies, including, but not limited to, naked proteins and nucleic acid molecules such as plasmids, bacterial artificial chromosomes, cosmids, naked DNA, mRNA, phage vectors, viral vectors.
The specification discloses the use of rAAV9 viruses whose genomes encode the cTuberin polypeptide (e.g. Examples 5 and 11).
Parameter 4
The claims are broad for failing to recite the dosage of the cTuberin protein pharmaceutical, nor cTuberin nucleic acid pharmaceutical, that is/are to be administered to the human and non-human subject/patient.
The specification is silent to cTuberin protein pharmaceutical dosages.
The specification discloses a nucleic acid dosage of 1x10^9 to 10x10^15 vector genome copies/kg body weight (e.g. pg 18, line 8).
The specification discloses the use of rAAV9 viruses whose genomes encode the cTuberin polypeptide at a dosage of about 4.5x10^12 genome copies/ml (e.g. Example 11).
Parameter 5
The claims are broad for reciting at a high level of generality a multitude of anatomically distinct routes, by which the cTuberin protein pharmaceutical or cTuberin nucleic acid pharmaceutical is to be administered to the human and non-human subject/patient, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
The specification discloses retro-orbital intravascular injection (e.g. pg 19, lines 8-9) or intracerebroventricular injection (e.g. Examples 5 and 11) of rAAV9.
Parameter 6
The claims are directed to treating tuberous sclerosis complex (TSC) diseases/disorders/conditions. The specification discloses TSC presents as enlargement and increased proliferation of cells, forming tumors affecting the brain, heart, kidneys, skin, and lungs, or causing developmental delay, autism, epilepsy, and hydrocephaly (e.g. pg 1, lines 21-26).
Parameter 7
The claims are broad for reciting “treating” at a high level of generality.
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question:
A therapeutically effective amount to do what?
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount (syn. subtherapeutic) to necessarily and predictably achieve a real-world, clinically meaningful treatment of a patient having tuberous sclerosis complex disease/disorder/condition.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin protein variant pharmaceuticals or cTuberin nucleic acid pharmaceuticals must be administered to the enormous genus of about 1x10^6 human and non-human animal subjects, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
Example 11 discloses intracerebroventricular or retro-orbital intravenous injection of 4.5x10^12 genome copies of a rAAV9-CBA-cTuberin vector to newborn Tsc2 mutant mice, thereby extending lifespan from 175 days to 185 days (Example 11; Figure 4A).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
The specification is silent to working examples of administering cTuberin protein pharmaceuticals, and dosages thereof.
The specification is silent to working examples of administering naked DNA, mRNA, bacteriophages, plasmids, cosmids, and bacterial artificial chromosomes that encode and express the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants, let alone SEQ ID NO:1 itself.
The claims fail to recite, and the specification fails to disclose, the structure/method step/function nexus of the therapeutically effective amount, syn. dosage, [parameter 4] of the genus of cTuberin protein pharmaceuticals and cTuberin nucleic acid pharmaceuticals [parameter 3] comprising the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] that are to be administered via the enormous genus of anatomically distinct routes [parameter 5] so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of tumors affecting the brain, heart, kidneys, skin, and lungs, or causing developmental delay, autism, epilepsy, and hydrocephaly [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, prevent the progression of disease, prevent spread of damage to uninjured cells, or prevent the mutations or defects [parameter 7] in the enormous genus of 1x10^6 human and non-human animal subjects [parameter 1].
The claims fail to recite, and the specification fails to disclose, a first cTuberin pharmaceutical, e.g. protein, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an animal patient [parameter 1], e.g. rabbit, via subcutaneous route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of increasing lifespan [parameter 7], as opposed to a second cTuberin pharmaceutical, e.g. protein, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an animal patient [parameter 1], e.g. horse, via oral inhalation route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of shrinking tumor size [parameter 7], for example.
The claims fail to recite, and the specification fails to disclose, a first cTuberin pharmaceutical, e.g. mRNA, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an human patient [parameter 1] via intramuscular route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of halting progression of a disease state [parameter 7], as opposed to a second cTuberin pharmaceutical, e.g. mRNA, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an animal patient [parameter 1], e.g. pig, via peritoneal route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of a decrease in mortality [parameter 7], for example.
The claims fail to recite, and the specification fails to disclose, a first cTuberin pharmaceutical, e.g. plasmid, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an bovine patient [parameter 1] via intrathecal route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of shrinking tumor size [parameter 7], as opposed to a second cTuberin pharmaceutical, e.g. bacteriophage, [parameter 3] of the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] and its corresponding dosage [parameter 4] that upon administration to an animal patient [parameter 1], e.g. parrot, via intubation route [parameter 5] will necessarily and predictably achieve the real-world and clinically meaningful result of slowing invasive growth of tumors [parameter 7], for example.
Applicant’s working examples are directed to the Tsc2 mutant mouse model system, wherein the mice are administered by intracerebroventricular or retro-orbital intravenous injection about 4.5x10^12 genome copies of an rAAV9 vector encoding the cTuberin protein having the amino acid sequence of SEQ ID NO:1 (758 amino acids in length) (Example 11).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial Tuberin polypeptide is to lack the Akt phosphorylation site T1462 does not tell you anything at all about the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity [parameter 2], and their corresponding protein or nucleic acid pharmaceutical [parameter 3] dosages [parameter 4], that upon administration via the enormous genus of anatomically distinct routes [parameter 5] to the enormous genus of about 1x10^6 human and non-human animals [parameter 1] will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results [parameter 7].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claims encompass the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity [parameter 2], and their corresponding protein or nucleic acid pharmaceutical [parameter 3] dosages [parameter 4], that upon administration via the enormous genus of anatomically distinct routes [parameter 5] to the enormous genus of about 1x10^6 human and non-human animals [parameter 1] will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results [parameter 7].
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
5. Claims 1-2, 4, 6-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a mouse patient having tuberous sclerosis complex (TSC), the method comprising the step of administering by intracerebroventricular or retro-orbital intravenous injection to said mouse patient at least 4.5x10^12 genome copies of a recombinant AAV9 virus whose genome encodes and expresses a condensed Tuberin protein having the amino acid sequence of SEQ ID NO:1,
does not reasonably provide enablement for methods of treating a human patient with an enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity, that, upon administration to the enormous genus of about 1x10^6 human and non-human patients via an enormous genus of anatomically distinct routes, will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The Examiner acknowledges that the instant 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection should have been made in the prosecution of parent application 16/613,907, now U.S. Patent 11,958,887, to wit, ‘887 claims 1, 5, 7-13, 15-17, and 19-21.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
Considering the mode of administration, the claims simply require administration of the cTuberin pharmaceutical to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols (Daya et al, Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Ghoraba et al (Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses, Clinical Opthalmology 16: 1753-1771, 2022) is considered relevant post-filing art for having taught that the associated immune and inflammatory reactions to gene therapy, including rAAV-based gene therapies, may render such treatment ineffective or harmful, which are of particular concerns for the eyes due to their susceptibility to inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors (Abstract). Intravitreal administration, while convenient, is unable to transduce the outer retina layers, which is the main target of most retinal diseases due to defects in the RPE or photoreceptor cells (e.g. pg 1762, Intravitreal Delivery). Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response. The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies (pg 1763, para 1).
Acland et al (U.S. 2004/0022766) is considered relevant prior art for having disclosed a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid [0023], and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5' inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a coding sequence encoding a human Lebercilin [0031].
Acland et al disclosed [0057] “[T]he use of subretinal injection as the route of delivery is a critical component of this method, as intravitreal administration does not enable the same therapeutic effects. The vector and carrier cannot diffuse across the multiple cell layers in the retina to reach the RPE, when intravitreal injection is used. Similarly, intravenous delivery is unacceptable because the material does not penetrate the blood-brain (blood-retina) barrier. Because the virus does not diffuse well, topical administration is similarly not preferred for this method.”
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
The specification fails to make up for the deficiencies of the global scientific community.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity, that upon administration to the enormous genus of human and non-human animals will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results.
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to extrapolate the results provided in the instant specification of administering at least 1x10^8 genome copies of an rAAV virus whose genome encodes and expresses SEQ ID NO:1 to the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity, that upon administration to the enormous genus of human and non-human animals, be it a protein pharmaceutical and/or the broad genus of nucleic acid pharmaceuticals, will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results.
Neither the specification nor the claims provide the appropriate protein dosage, nucleic acid vector dosage, nor viral dosage to be administered in the multitude of anatomically and physiologically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration means that would reasonably be expected by the ordinary artisan to necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC, including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results.
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible AAV serotypes disclosed), routes of administration (as disclosed, do not even require direct administration to the diseased tissue), the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), the specific genes to be used for a treatment (the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants), the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
The instant portion of the invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be workable". The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". (See Genentech Inc v. Novo Nordisk A/S 42 USPQ2d 1001, at 1005). The claimed methods of using the nucleic acid molecules, including AAV vectors, encoding the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants to necessarily and predictably sufficiently treat TSC constitutes such a "germ of an idea".
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make mouse studies work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The specification fails to make up for the deficiencies of the global scientific community.
Applicant’s working examples are directed to the Tsc2 mutant mouse model system, wherein the mice are administered by intracerebroventricular or retro-orbital intravenous injection about 4.5x10^12 genome copies of an rAAV9 vector encoding the cTuberin protein having the amino acid sequence of SEQ ID NO:1 (758 amino acids in length) (Example 11).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial Tuberin polypeptide is to lack the Akt phosphorylation site T1462 does not tell you anything at all about the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity [parameter 2], and their corresponding protein or nucleic acid pharmaceutical [parameter 3] dosages [parameter 4], that upon administration via the enormous genus of anatomically distinct routes [parameter 5] to the enormous genus of about 1x10^6 human and non-human animals [parameter 1] will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results [parameter 7].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claims encompass the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants having the functional properties of binding hamartin and/or having GTPase-activating (GAP) activity [parameter 2], and their corresponding protein or nucleic acid pharmaceutical [parameter 3] dosages [parameter 4], that upon administration via the enormous genus of anatomically distinct routes [parameter 5] to the enormous genus of about 1x10^6 human and non-human animals [parameter 1] will necessarily and predictably achieve a real-world, clinically meaningful treatment of TSC [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, or other beneficial or desired clinical results [parameter 7].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The claims fail to recite, and the specification fails to disclose, the structure/method step/function nexus of the therapeutically effective amount, syn. dosage, [parameter 4] of the genus of cTuberin protein pharmaceuticals and cTuberin nucleic acid pharmaceuticals [parameter 3] comprising the enormously vast genus of about 3x10^235, 3x10^58, and/or 5x10^37 structurally and functionally undisclosed cTuberin polypeptide variants [parameter 2] that are to be administered via the enormous genus of anatomically distinct routes [parameter 5] so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of tumors affecting the brain, heart, kidneys, skin, and lungs, or causing developmental delay, autism, epilepsy, and hydrocephaly [parameter 6], including, but not limited to, reversing, alleviating, inhibiting, slowing, stopping the progression of a symptom, stopping the severity of a symptom, reducing at least one adverse effect or symptom, alleviating at least one adverse effect or symptom, reduce progression of a disease state, halt progression of a disease state, shrinking tumor size, delay invasive growth of tumors, slow invasive growth of tumors, a decrease in mortality, an increase in lifespan, prevent the progression of disease, prevent spread of damage to uninjured cells, or prevent the mutations or defects [parameter 7] in the enormous genus of 1x10^6 human and non-human animal subjects [parameter 1].
Applicant’s working examples are directed to the Tsc2 mutant mouse model system, wherein the mice are administered by intracerebroventricular or retro-orbital intravenous injection about 4.5x10^12 genome copies of an rAAV9 vector encoding the cTuberin protein having the amino acid sequence of SEQ ID NO:1 (758 amino acids in length) (Example 11).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that limiting the claimed invention to a method of treating a mouse patient having tuberous sclerosis complex (TSC), the method comprising the step of administering by intracerebroventricular or retro-orbital intravenous injection to said mouse patient at least 4.5x10^12 genome copies of a recombinant AAV9 virus whose genome encodes and expresses a condensed Tuberin protein having the amino acid sequence of SEQ ID NO:1, is proper.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
6. Claim(s) 1-2, 4, 7, 12, and 21-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Inoki et al (Nature Cell Biology 4: 648-657, 2002; of record in parent application 16/613,907), as evidenced by GenBank XP006245971 (2016; of record in parent application 16/613,907).
Claim interpretation: Claim 1 recites an engineered condensed tuberin (cTuberin) polypeptide comprising:
a) a hamartin binding region;
b) a GAP region; and
c) lacking an Akt phosphorylation site corresponding to coordinate Thr 1462 of human Tuberin.
As discussed above in the 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection, the adjective “condensed” is relative terminology. The breadth of “condensed” is considered to encompass Tuberin polypeptides merely lacking a single amino acid.
With respect to Claim 1, Inoki et al is considered relevant prior art for having taught a condensed rat TSC2 polypeptide comprising S1422 and T1466 (Figure 4a), whereby those of ordinary skill in the art recognized that rat T1466 (long form; syn. T1422, short form) corresponds to T1462 in human TSC2 (as evidenced by GenBank NG_005895; alignment provided below):
Human: SSSPRSPSGLRPRGYTISDSAPSRRGKRVE
rat: sssprspsglrprgytisdsapsrrgkrve
Inoki et al taught modification of the rat cTuberin to lack the Akt phosphorylation site at T1422, alone (A4) or in combination with removing other Akt phosphorylation sites (6A, Figure 4b; syn. human T1462).
Both the long and short forms of the rat TSC2 polypeptide inherently and naturally comprise:
a) a hamartin binding region; and
b) a GAP region (e.g. Figure 4a).
With respect to Claim 2, the rat TSC2 hamartin binding domain inherently and naturally has at least 94% identity to instant SEQ ID NO:2, as shown below.
Query Match 94.0%
1 MAKPTSKDSGLKEKFKILLGLGTPRPNPRSAEGKQTEFIITAEILRELSMECGLNNRIRM 60
||||||||||||||||||||||| ||||| ||||||||||||||||||| ||||||||||
1 MAKPTSKDSGLKEKFKILLGLGTSRPNPRCAEGKQTEFIITAEILRELSGECGLNNRIRM 60
61 IGQICEVAKTKKFEEHAVEALWKAVADLLQPERPLEARHAVLALLKAIVQGQGERLGVLR 120
|||||:|||||| ||||||||||||:|||||||| ||||||||||||||||||:||||||
61 IGQICDVAKTKKLEEHAVEALWKAVSDLLQPERPPEARHAVLALLKAIVQGQGDRLGVLR 120
121 ALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELADFVLQWMDVGLSSEFLLVL 180
|||||||||||||||||||||||||||||||||||||||||:||||||||||||||||||
121 ALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELAEFVLQWMDVGLSSEFLLVL 180
181 VNLVKFNSCYLDEYIARMVQMICLLCVRTASSVDIEVSLQVLDAVVCYNCLPAESLPLFI 240
|||||||||||||||| || ||||||:|| ||||||||||||||||||||||||||||||
181 VNLVKFNSCYLDEYIAPMVHMICLLCIRTVSSVDIEVSLQVLDAVVCYNCLPAESLPLFI 240
241 VTLCRTINVKELCEPCWKLMRNLLGTHLGHSAIYNMCHLMEDRAYMEDAPLLRGAVFFVG 300
:|||||:|||||||||||||||||||||||||||||| :||:|:||||||||||||||||
241 ITLCRTVNVKELCEPCWKLMRNLLGTHLGHSAIYNMCRIMENRSYMEDAPLLRGAVFFVG 300
301 MALWGAHRLYSLRNSPTSVLPSFYQAMACPNEVVSYEIVLSITRLIKKYRKELQVVAWDI 360
||||||||||||:|||||||||||:|| |||||||||||||||||||||||||| | |||
301 MALWGAHRLYSLKNSPTSVLPSFYEAMTCPNEVVSYEIVLSITRLIKKYRKELQAVTWDI 360
361 LLNIIERLLQQLQTLDSPELRTIVHDLLTTVEELCDQNEFHGSQERYFELVERCADQRPE 420
||:|||||||||| |||||||||||||||||||||||||||||||||:|||| ||||||
361 LLDIIERLLQQLQNLDSPELRTIVHDLLTTVEELCDQNEFHGSQERYYELVESYADQRPE 420
421 SSLLNLISYRAQSIHPAKDGWIQNLQALME 450
|||||||:|||||||||||||||||| |||
421 SSLLNLITYRAQSIHPAKDGWIQNLQLLME 450
With respect to Claim 4, the rat TSC2 GAP domain inherently and naturally has at least 93% identity to instant SEQ ID NO:2, as shown below.
Query Match 92.8%
1 KPILLPNESQSFERSVQLLDQIPSYDTHKIAVLYVGEGQSNSELAILSNEHGSYRYTEFL 60
|||||||| ||||||||||||||||||||||||||||||:|||||||||||||||||||
1 KPILLPNE--SFERSVQLLDQIPSYDTHKIAVLYVGEGQSSSELAILSNEHGSYRYTEFL 58
61 TGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFHIATLMPTKDVDKHRC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
59 TGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFHIATLMPTKDVDKHRC 118
121 DKKRHLGNDFVSIVYNDSGEDFKLGTIKGQFNFVHVIVTPLDYECNLVSLQCRKDMEGLV 180
|||||||||||||:|||||||||||||||||||||||:|||||:|||::|||||||||||
119 DKKRHLGNDFVSIIYNDSGEDFKLGTIKGQFNFVHVIITPLDYKCNLLTLQCRKDMEGLV 178
181 DTSVAKIVSDRNLPFVARQMALHANMASQVHHSRSNPTDIYPSKWIARLRHIKRLRQRIC 240
||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||
179 DTSVAKIVSDRNLSFVARQMALHANMASQVHHSRSNPTDIYPSKWIARLRHIKRLRQRIR 238
241 EEAAYSNPSLPLVHPPSHSKAPAQTPAEPTPGYEVGQRKRLISSVEDFTEFV 292
|| ||||||||:|||:|:| ||| | | || || ||||||||||:||||||
239 EEVHYSNPSLPLMHPPAHTKVPAQAPTEATPTYETGQRKRLISSVDDFTEFV 290
With respect to Claim 7, the instant specification fails to define a “spacer”. Inoki et al taught the rat cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4a).
With respect to Claim 12, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Thus, Inoki et al anticipate the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
7. Claim(s) 1-5, 7, 12-14, 21-23, 30-31, and 35 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record in parent application 16/613,907) in view of GenBank XP006245971 (2016; of record in parent application 16/613,907) and Lo et al (U.S. 2012/0252877; of record in parent application 16/613,907).
With respect to Claim 1, Inoki et al is considered relevant prior art for having taught a condensed rat TSC2 polypeptide comprising S1422 and T1466 (Figure 4a), whereby those of ordinary skill in the art recognized that rat T1466 (long form; syn. T1422, short form) corresponds to T1462 in human TSC2 (as evidenced by GenBank NG_005895; of record; alignment provided below):
Human: SSSPRSPSGLRPRGYTISDSAPSRRGKRVE
rat: sssprspsglrprgytisdsapsrrgkrve
Inoki et al taught modification of the rat cTuberin to lack the Akt phosphorylation site at T1422, alone (A4) or in combination with removing other Akt phosphorylation sites (6A, Figure 4b; syn. human T1462).
Both the long and short forms of the rat TSC2 polypeptide inherently and naturally comprise:
a) a hamartin binding region; and
b) a GAP region (e.g. Figure 4a).
Inoki et al do not teach the nucleic acid encoding cTuberin is present in a viral expression vector.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 23 and 30-31, Lo et al is considered relevant prior art for having disclosed a method of treating Tuberous Sclerosis Complex in a patient, the method comprising the step of administering to said patient a rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract, [0010-11]).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cloning, genetics, and the creation of transgenic cells. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first expression vector, e.g. plasmid, as taught by Inoki et al, with a second expression vector, i.e., a viral expression vector, including more specifically, an rAAV expression vector, as disclosed by Lo et al, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first expression vector, e.g. plasmid, with a second expression vector, i.e., a viral expression vector, including more specifically, an rAAV expression vector, because those of ordinary skill in the art had long-recognized and successfully reduced to practice the ability to express their transgene(s) of interest in a different expression vectors, including plasmids and rAAV expression vectors, both of which have long-been commercially available, and Lo et al successfully reduced to practice the ability to express Tuberin variants from an rAAV expression vector. Inoki et al taught that disease-derived TSC2 mutations showed decreased ability to inhibit S6K phosphorylation (pg 650, col. 1), Lo et al disclosed that TSC2, or variants thereof, delivered via an rAAV can treat TSC [0010-11], in effect, therapeutic TSC2 gene rescue with functional TSC2, and Inoki et al taught that, as discussed above, the cTuberin polypeptide comprising Akt mutations are functionally the same as wildtype TSC2 (Tuberin) in its abilities to complex with TSC1, inhibit S6K, and inhibit 4E-BP1, whereby such functionalities correlates with its tumor suppressor function (pg 648, col. 2).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 2-3, the rat TSC2 hamartin binding domain inherently and naturally has at least 94% identity to instant SEQ ID NO:2, as shown below.
Query Match 94.0%
1 MAKPTSKDSGLKEKFKILLGLGTPRPNPRSAEGKQTEFIITAEILRELSMECGLNNRIRM 60
||||||||||||||||||||||| ||||| ||||||||||||||||||| ||||||||||
1 MAKPTSKDSGLKEKFKILLGLGTSRPNPRCAEGKQTEFIITAEILRELSGECGLNNRIRM 60
61 IGQICEVAKTKKFEEHAVEALWKAVADLLQPERPLEARHAVLALLKAIVQGQGERLGVLR 120
|||||:|||||| ||||||||||||:|||||||| ||||||||||||||||||:||||||
61 IGQICDVAKTKKLEEHAVEALWKAVSDLLQPERPPEARHAVLALLKAIVQGQGDRLGVLR 120
121 ALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELADFVLQWMDVGLSSEFLLVL 180
|||||||||||||||||||||||||||||||||||||||||:||||||||||||||||||
121 ALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELAEFVLQWMDVGLSSEFLLVL 180
181 VNLVKFNSCYLDEYIARMVQMICLLCVRTASSVDIEVSLQVLDAVVCYNCLPAESLPLFI 240
|||||||||||||||| || ||||||:|| ||||||||||||||||||||||||||||||
181 VNLVKFNSCYLDEYIAPMVHMICLLCIRTVSSVDIEVSLQVLDAVVCYNCLPAESLPLFI 240
241 VTLCRTINVKELCEPCWKLMRNLLGTHLGHSAIYNMCHLMEDRAYMEDAPLLRGAVFFVG 300
:|||||:|||||||||||||||||||||||||||||| :||:|:||||||||||||||||
241 ITLCRTVNVKELCEPCWKLMRNLLGTHLGHSAIYNMCRIMENRSYMEDAPLLRGAVFFVG 300
301 MALWGAHRLYSLRNSPTSVLPSFYQAMACPNEVVSYEIVLSITRLIKKYRKELQVVAWDI 360
||||||||||||:|||||||||||:|| |||||||||||||||||||||||||| | |||
301 MALWGAHRLYSLKNSPTSVLPSFYEAMTCPNEVVSYEIVLSITRLIKKYRKELQAVTWDI 360
361 LLNIIERLLQQLQTLDSPELRTIVHDLLTTVEELCDQNEFHGSQERYFELVERCADQRPE 420
||:|||||||||| |||||||||||||||||||||||||||||||||:|||| ||||||
361 LLDIIERLLQQLQNLDSPELRTIVHDLLTTVEELCDQNEFHGSQERYYELVESYADQRPE 420
421 SSLLNLISYRAQSIHPAKDGWIQNLQALME 450
|||||||:|||||||||||||||||| |||
421 SSLLNLITYRAQSIHPAKDGWIQNLQLLME 450
GenBank NG_005895 (of record) evidences that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a hamartin binding region that is 100% identical to the amino acid sequence SEQ ID NO: 2.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding hamartin binding region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
Lo et al disclosed human TSC2 polypeptide amino acid sequence ([0043], SEQ ID NO:3), which comprises an amino acid sequence that is 100% identical to the hamartin binding region of SEQ ID NO:2.
With respect to Claims 4-5, the rat TSC2 GAP domain inherently and naturally has at least 93% identity to instant SEQ ID NO:2, as shown below.
Query Match 92.8%
1 KPILLPNESQSFERSVQLLDQIPSYDTHKIAVLYVGEGQSNSELAILSNEHGSYRYTEFL 60
|||||||| ||||||||||||||||||||||||||||||:|||||||||||||||||||
1 KPILLPNE--SFERSVQLLDQIPSYDTHKIAVLYVGEGQSSSELAILSNEHGSYRYTEFL 58
61 TGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFHIATLMPTKDVDKHRC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
59 TGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFHIATLMPTKDVDKHRC 118
121 DKKRHLGNDFVSIVYNDSGEDFKLGTIKGQFNFVHVIVTPLDYECNLVSLQCRKDMEGLV 180
|||||||||||||:|||||||||||||||||||||||:|||||:|||::|||||||||||
119 DKKRHLGNDFVSIIYNDSGEDFKLGTIKGQFNFVHVIITPLDYKCNLLTLQCRKDMEGLV 178
181 DTSVAKIVSDRNLPFVARQMALHANMASQVHHSRSNPTDIYPSKWIARLRHIKRLRQRIC 240
||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||
179 DTSVAKIVSDRNLSFVARQMALHANMASQVHHSRSNPTDIYPSKWIARLRHIKRLRQRIR 238
241 EEAAYSNPSLPLVHPPSHSKAPAQTPAEPTPGYEVGQRKRLISSVEDFTEFV 292
|| ||||||||:|||:|:| ||| | | || || ||||||||||:||||||
239 EEVHYSNPSLPLMHPPAHTKVPAQAPTEATPTYETGQRKRLISSVDDFTEFV 290
GenBank NG_005895 (of record; of record in parent application 16/613,907) evidences that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a GTPase-activating protein (GAP) region that is 100% identical to the amino acid sequence SEQ ID NO: 3.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding GTPase-activating protein (GAP) region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
Lo et al disclosed human TSC2 polypeptide amino acid sequence ([0043], SEQ ID NO:3), which comprises an amino acid sequence that is 100% identical to the GAP region of SEQ ID NO:3.
With respect to Claim 7, the instant specification fails to define a “spacer”. Inoki et al taught the rat cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4a).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137], and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
With respect to Claim 23, Lo et al disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract), said rAAV comprising an AAV capsid and AAV genome [0026, 91-92].
With respect to Claim 30, Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
With respect to Claim 35, Lo et al disclosed wherein said patient has a renal angiomyolipoma [0017].
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
8. Claim(s) 12-14 and 21-23 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record in parent application 16/613,907) in view of GenBank XP006245971 (2016; of record in parent application 16/613,907) and Lo et al (U.S. 2012/0252877; of record in parent application 16/613,907), as applied to Claims 1-5, 7, 12-14, 21-23, 30-31, and 35 above, and in further view of Ward et al (Blood 117(3): 798-807, 2011; of record in parent application 16/613,907).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Inoki et al nor Lo et al teach/disclose ipsis verbis wherein the nucleic acid encoding TSC2 is codon-optimized for expression in human cells.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 13-14, Ward et al is considered relevant prior art for having taught the codon optimization of a therapeutic transgene for expression in a human cell (Title), whereby said codon-optimized transgene is operably linked to a regulatory control sequence (Figure 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a nucleic acid encoding a therapeutic TSC2 (syn. Tuberin) polypeptide to be codon-optimized for expression in human cells with a reasonable expectation of success, the artisan being motivated to do so because the scientific and technical concept(s) of codon-optimization has long-been recognized by the ordinary artisan, and Ward et al successfully demonstrated the ability to codon-optimize a therapeutic transgene for expression in human cells, whereby said codon-optimization “leads to high-level expression” (Title).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137], and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title).
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
With respect to Claim 23, Lo et al disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract), said rAAV comprising an AAV capsid and AAV genome [0026, 91-92].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector, be it lentiviral vector or rAAV viral vector (e.g. Figure 1; pg 806, col. 1).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
9. Claim(s) 8, 12-14, and 21-22 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank XP006245971 (2016; of record), Lo et al (U.S. 2012/0252877; of record), and Ward et al (2011; of record), as applied to Claims 1-5, 7, 12-14, 21-23, 30-31, and 35 above, and in further view of Yokoi et al (U.S. Patent 6,884,419; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
As discussed supra, the instant specification fails to define a “spacer”. Inoki et al taught the rat cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4a).
Neither Inoki et al, Lo et al, nor Ward et al teach/disclose wherein said spacer comprises at least SGGG, more specifically, said spacer is SEQ ID NO: 4.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 8, Yokoi et al is considered relevant prior art for having disclosed the use of spacer linkers when constructing a fusion protein, said spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 (Table 4; (SGGG)4).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first spacer domain in a cTuberin polypeptide with a second spacer domain, to wit, spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 ((SGGG)4)) with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first spacer domain in a cTuberin polypeptide with a second spacer domain, to wit, spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 ((SGGG)4)) because those of ordinary skill in the art previously recognized the scientific and technical concepts of using compact spacer motifs, including (SGGG)4, as disclosed by Yokoi et al, in the construction of synthetic polypeptides, wherein said spacer motif allows/does not inhibit the activities of the first and second polypeptide domains linked together by said spacer motif (Yokoi et al, col. 4, lines 52-54), whereby (SGGG)4 spacer was previously recognized in the art to ensure sufficient spacing for proper peptide structure of each active domain upon expression.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137] and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title).
Yokoi et al disclosed a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 1).
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
Yokoi et al disclosed animal cells transduced or transfected with a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 2).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
Yokoi et al disclosed animal cells transduced or transfected with a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 2).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
10. Claim(s) 48 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank XP006245971 (2016; of record), Lo et al (U.S. 2012/0252877; of record), Ward et al (2011; of record), and Yokoi et al (U.S. Patent 6,884,419; of record), as applied to Claims 1-5, 7-8, 12-14, 21-23, 30-31, and 35 above, and in further view of Babchia et al (Invest. Ophthalmol. & Vis. Sci. 51(1): 421-429, 2010; of record in parent application 16/613,907) and Ji et al (Journal of Cancer 8(4): 555-562, doi:10.7150/jca.17205; 8 pages, published online February 11, 2017; of record in parent application 16/613,907).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Inoki et al taught that Akt inhibitor LY294002 decreases the phosphorylation of Tuberin at the same Akt phosphorylation sites studied by Inoki et al (pg 651, col. 1). Thus, the ordinary artisan would have recognized the cTuberin polypeptide comprising Akt mutations, not phosphorylated by Akt, and thus a functional inhibitor of Akt, are functionally the same as wildtype TSC2 (Tuberin) in its abilities to complex with TSC1, inhibit S6K, and inhibit 4E-BP1, whereby such functionalities correlates with its tumor suppressor function (pg 648, col. 2).
Neither Inoki et al, Lo et al, Ward, nor Yokoi et al teach/disclose wherein the method of treating TSC comprises administration of rapamycin.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 48, Babchia et al is considered relevant prior art for having taught a method of treating cancer cells comprising the step of inhibiting Akt (via Ly294002) in combination with the step of inhibiting mTOR (via rapamycin), whereby the combination of the Akt inhibitor and the mTOR inhibitor yields a greater (synergistic) inhibition of cell proliferation than either Akt inhibitor or the mTOR inhibitor individually (e.g. Figure 3c; pg 425, col. 2, “synergistic effects”).
Ji et al is considered relevant prior art for having taught a method of treating TSC, the method comprising the step of inhibiting Akt (via MK-2206) in combination with the step of inhibiting mTOR (via rapamycin), whereby the Akt inhibitor increased cytotoxicity of rapamycin (Abstract) and a synergistic effect (pg 556, col. 1, “synergistic effect was detected”).
Both Babchia et al and Ji et al taught that rapamycin treatment alone activates Akt (Babchia et al, pg 421, col. 1, Results; Ji et al, pg 561, col. 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to combine a cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) with rapamycin in a method of treating TSC with a reasonable expectation of success because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. An artisan would be motivated to combine a cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) with rapamycin in a method of treating TSC because the ordinary artisan would have recognized the scientific and technical concepts that:
i) rapamycin treatment alone activates Akt (Babchia et al, pg 421, col. 1, Results; Ji et al, pg 561, col. 2);
ii) rapamycin treatment had been previously anticipated to be effective in the treatment of TSC, but in practice has only demonstrated modest clinical efficacy (Ji et al, pg 556, col. 1);
iii) the cTuberin polypeptide comprising Akt mutations is not phosphorylated by Akt, and thus is a functional inhibitor of Akt (Inoki et al); and
iv) both Babchia et al and Ji et al successfully demonstrated therapeutic methods, including in a method of treating TSC (Ji et al), using an Akt inhibitor in combination with a mTOR inhibitor (rapamycin), whereby the combination yielded a synergistic improvement and/or decreased rapamycin cytotoxicity (Babchia et al, Ji et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
11. Claims 1-7, 10, 12-14, 18, and 21-22 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank (NG_005895; January 31, 2016; of record) and Guvakova et al (Cell Movement: New Research Trends, Chapter VI, pgs 187-207, 2009, editors T. Abreau and G. Silva, Nova Science Publishers, Inc, ISBN: 978-1-60692-570-6; of record in parent application 16/613,907), and Nellist et al (Eur. J. Human Genetics 13: 59-68, 2005; of record in parent application 16/613,907).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Inoki et al is considered relevant prior art for having taught a condensed rat TSC2 polypeptide comprising S1422 and T1466 (Figure 4a), whereby those of ordinary skill in the art recognized that rat T1466 (long form; syn. T1422, short form) corresponds to T1462 in human TSC2 (as evidenced by GenBank NG_005895; alignment provided below):
Human: SSSPRSPSGLRPRGYTISDSAPSRRGKRVE
rat: sssprspsglrprgytisdsapsrrgkrve
Inoki et al taught modification of the rat cTuberin to lack the Akt phosphorylation site at T1422, alone (A4) or in combination with removing other Akt phosphorylation sites (6A, Figure 4b; syn. human T1462).
Both the long and short forms of the rat TSC2 polypeptide inherently and naturally comprise:
a) a hamartin binding region; and
b) a GAP region (e.g. Figure 4a).
GenBank NG_005895 evidence that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s).
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding amino acid variant in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed, and also the corresponding nucleic acid sequence to encode said human cTuberin polypeptide.
GenBank NG_005895 teaches that R451 is encoded by Exon 13, and S1514 is encoded by Exon 35.
Inoki et al taught Akt phosphorylation sites at S939 (syn. Hu S939, S981, S993, S1130, S1132, T1422 (syn. Hu T1462), and T1460, and thus the ordinary artisan would recognize that deletion of at least 939-1462 would remove all of the Akt phosphorylation sites.
Inoki et al do not teach wherein said cTuberin lacks amino acids 451-1514 of human tuberin (SEQ ID NO: 10).
However, prior to the effective filing date of the instantly claimed invention, Guvakova et al is considered relevant prior art for having taught that the TSC2 hamartin binding domain terminates around amino acid 418, and taught a fusion protein comprising the hamartin binding domain of amino acids 1-460 of TSC2 (Figure 4, HBD-TSC2). Guvakova et al also taught that the TSC2 GAP domain begins around amino acid 1517 (Figure 4, legend, GAP domain amino acids 1517-1674), illustrating more specifically beginning at amino acid 1531.
Nellist et al is considered relevant prior art for having demonstrated synthesis of a condensed Tuberin (cTuberin TSC2 variant) comprising an internal, in-frame deletions (TSC2 cDNA encoding amino acids 1-252 plus 1536-1784; pg 60, col. 1), which would comprise part of the hamartin binding domain, lacking amino acids 451-1514 of human Tuberin (including an Akt phosphorylation site Thr 1462), and comprises the GAP domain.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a rat cTuberin comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site T1462 (syn. rat T1422), as taught by Inoki et al, with a human cTuberin comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site T1462 with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a rat cTuberin comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site T1462 (syn. rat T1422) with a human cTuberin comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site T1462 because the ordinary artisans previously recognized that Tuberous Sclerosis Complex (TSC) disorders exist in humans (Inoki et al, pg 648 Introduction).
Inoki et al taught that TSC1/TSC2 complex formation is important for their biological functions, and disease-associated mutations in TSC2 weaken the interaction with TSC1 (pg 651, col. 2-pg 653, col. 1, joining ¶). Similarly, phosphorylation by Akt inhibits TSC2 function (pg 651, col. 2).
Nutrient stimulation of S6K is inhibited by TSC1/TSC2 complex.
Phosphorylation of 4E-BP1 is inhibited by TSC1/TSC2 complex.
TSC2 phosphorylation mimetics of Akt sites have decreased ability to inhibit S6K; whereas, Akt-mutant TSC2 enhanced its ability to inhibit S6K;
TSC2 phosphorylation mimetics of Akt sites have decreased ability to inhibit phosphorylation of downstream target 4E-BP1; whereas, Akt-mutant TSC2 enhanced its ability to inhibit phosphorylation of 4E-BP1;
TSC2 phosphorylation mimetics of Akt sites weaken interaction with TSC1; whereas, Akt-mutant TSC2 is fully capable of interacting with TSC1;
TSC2 phosphorylation mimetics of Akt sites are less stable expression; whereas, Akt-mutant TSC2 are less ubiquitinated and more stable expression.
Inoki et al taught that Akt-dependent phosphorylation inhibits the function of TSC2 by destabilizing its association with TSC1, thus promoting ubiquitin-mediated degradation (pg 654, col. 1).
Inoki et al taught that their results provide a possible mechanism for the regulation of S6K by Akt, whereby TSC1/TSC2 complex functions downstream of Akt and upstream of mTOR to control S6K and 4E-BP1 activities in mammalian cells (pg 654, col. 2), whereby S6K and 4E-BP1 are key regulators of translation and cell growth, being inhibited by TSC1/TSC2. This activity is probably important for their physiological functions because it is compromised by disease-associated TSC2 mutations (pg 655).
Inoki et al taught that the S6K and 4E-BP1 phosphorylation assays as taught using the rat TSC2 system provide a simple and relevant functional assay for TSC1–TSC2 and will significantly aid future investigation of these tumour suppressor proteins. The data here suggest a molecular basis for how TSC1/TSC2 complex functions as a tumor suppressor to inhibit cell growth via inhibition of mTOR, S6K, and 4E-BP1 activity (pg 655). The ordinary artisan would recognize that making the corresponding rat TSC2 Akt-mutants in the human TSC2 protein would be more appropriate and relevant to assess the function of human TSC2 in the context of human cell biology mechanism and human disease.
It also would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.”
Those of ordinary skill in the art previously recognized the amino acid sequence of human TSC2, and the amino acid domains that comprise the hamartin binding domain and the GAP domain, and the ordinary artisan could have pursued the known potential options with a reasonable expectation of success, as demonstrated by the intentional creation of amino acid substitutions (Inoki et al), intentional creation of fusion proteins comprising different TSC2 sub-domains for functional assays (Guvakova et al).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
The cited prior art evidence that those of ordinary skill in the art would have recognized that a condensed human (TSC2) Tuberin (cTuberin) comprising a hamartin binding domain and a GAP domain, but lacking, at least, the Akt phosphorylation site T1462 would be achieved with a cTuberin polypeptide lacking the domains between the N-terminal hamartin binding domain and the C-terminal GAP domain.
Inoki et al taught Akt phosphorylation sites at S939 (syn. Hu S939, S981, S993, S1130, S1132, T1422 (syn. Hu T1462), and T1460, and thus the ordinary artisan would recognize that deletion of at least 939-1462 would remove all of the Akt phosphorylation sites.
Guvakova et al taught the hamartin binding domain terminates around amino acid 418, whereby GenBank NG_005895 teaches that Exon 12 terminates with R418.
Guvakova et al taught the GAP domain begins around amino acid 1531, more specifically 1517, whereby GenBank NG_005895 teaches that Exon 35 begins at F1499, and encodes P1517.
Nellist et al demonstrated synthesis of a condensed Tuberin (cTuberin TSC2 variant) comprising an internal, in-frame deletions (TSC2 cDNA encoding amino acids 1-252 plus 1536-1784; pg 60, col. 1), which would comprise part of the hamartin binding domain, lacking amino acids 451-1514 of human Tuberin (including an Akt phosphorylation site Thr 1462), and comprises the GAP domain.
In light of GenBank NG_005895, the ordinary artisan would have recognized that deletion of amino acids 418-1498 would yield a cTuberin polypeptide comprising the N-terminal hamartin binding domain and the C-terminal GAP domain, and remove all of the Akt phosphorylation sites, including T1462.
In light of Guvakova et al, the ordinary artisan would have recognized that deletion of amino acids 418-1516, 460-1516, or 418-1531, would yield a cTuberin polypeptide comprising the N-terminal hamartin binding domain and the C-terminal GAP domain, and remove all of the Akt phosphorylation sites, including T1462.
Nellist et al successfully demonstrated the ability to express a cTuberin in which at least amino acids 418-1514 are deleted, essentially placing a portion of the hamartin binding domain adjacent to the GAP domain.
The instant specification fails to disclose an element of criticality for a cTuberin polypeptide comprising the N-terminal hamartin binding domain and the C-terminal GAP domain, and a deletion of amino acids 451-1514, which removes all of the Akt phosphorylation sites, including T1462.
Furthermore, instant independent Claim 1 merely requires that 451-1514 be deleted, and allows for additional amino acids to be deleted, as would be achieved in the 418-1516 and/or 418-1531 deletions per the Guvakova et al.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
There is no disclosed element of criticality for a deletion of 451-1514 (instant), as opposed to 460-1516 (Guvakova et al), which comprises a mere addition of nine N-terminal amino acids and additional deletion of two C-terminal amino acids.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 2-3, GenBank NG_005895 evidence that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a hamartin binding region that is 100% identical to the amino acid sequence SEQ ID NO: 2.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding hamartin binding region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
With respect to Claims 4-5, GenBank NG_005895 evidence that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a GTPase-activating protein (GAP) region that is 100% identical to the amino acid sequence SEQ ID NO: 3.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding GTPase-activating protein (GAP) region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
With respect to Claim 7, the instant specification fails to define a “spacer”. Inoki et al taught the rat cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4a).
Guvakova et al taught the human cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Guvakova et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region (Figure 4, expression constructs), expressed in human cells (e.g. pg 190, Methods, Cells), and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Nellist et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region (pg 60, col. 1, expression constructs), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Guvakova et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. MCF-7 cells (Figure 5, legend).
Nellist et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. mouse embryo fibroblast cells (Figure 4d, legend).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Guvakova et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Nellist et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
With respect to Claim 10, directed to a human cTuberin (syn. condensed TSC2) having the amino acid sequence at least 90% identical to SEQ ID NO: 1 (758 amino acids), and thus allows for deletions, insertions, additions, or substitutions of up to 76 amino acids, which are encompassed by:
i) deletion of amino acids 418-1498 (GenBank NG_005895; difference of 33 N-terminal amino acids and 16 C-terminal amino acids);
ii) deletion of amino acids 418-1516 (Guvakova et al; difference of 33 N-terminal amino acids and 2 C-terminal amino acids);
iii) deletion of amino acids 460-1516 (Guvakova et al; difference of 9 N-terminal amino acids and 2 C-terminal amino acids); and
iv) deletion of amino acids 418-1531 (Guvakova et al; difference of 33 N-terminal amino acids and 17 C-terminal amino acids), all of which would yield a cTuberin polypeptide comprising the N-terminal hamartin binding domain and the C-terminal GAP domain, and remove all of the Akt phosphorylation sites, including T1462.
With respect to Claim 18, the claim is directed to a genus of polynucleotides having at least 90% identity to SEQ ID NO:5 (2306 nts), which encodes the amino acid sequence of SEQ ID NO:1. In accordance with the discussion supra re: Claim 10, those of ordinary skill in the art previously knew the nucleotide sequence of human TSC2, and thus the deletion embodiments reasonably inferred by GenBank NG_005895, Guvakova et al, and Nellist et al would naturally yield thus-encoding polynucleotides having at least 90% identity to instant SEQ ID NO:5.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
12. Claims 2-5, 12-14, 21-23, 30-31, and 35 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank (NG_005895; January 31, 2016) and Guvakova et al (2009; of record), and Nellist et al (2005; of record), as applied to Claims 1-7, 10, 12-14, 18, and 21-22 above, and in further view of Lo et al (U.S. 2012/0252877; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Inoki et al, Guvakova et al, nor Nellist et al teach the nucleic acid encoding cTuberin is present in a viral expression vector.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 21 and 30-31, Lo et al is considered relevant prior art for having disclosed a method of treating Tuberous Sclerosis Complex in a patient, the method comprising the step of administering to said patient a rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract, [0010-11]).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first expression vector, e.g. plasmid, as taught by Inoki et al, with a second expression vector, i.e., a viral expression vector, including more specifically, an rAAV expression vector, as disclosed by Lo et al, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first expression vector, e.g. plasmid, with a second expression vector, i.e., a viral expression vector, including more specifically, an rAAV expression vector, because those of ordinary skill in the art had long-recognized and successfully reduced to practice the ability to express their transgene(s) of interest in a different expression vectors, including plasmids and rAAV expression vectors, both of which have long-been commercially available, and Lo et al successfully reduced to practice the ability to express Tuberin variants from an rAAV expression vector. Inoki et al taught that disease-derived TSC2 mutations showed decreased ability to inhibit S6K phosphorylation (pg 650, col. 1), Lo et al disclosed that TSC2, or variants thereof, delivered via an rAAV can treat TSC [0010-11], in effect, therapeutic TSC2 gene rescue with functional TSC2, and Inoki et al taught that, as discussed above, the cTuberin polypeptide comprising Akt mutations are functionally the same as wildtype TSC2 (Tuberin) in its abilities to complex with TSC1, inhibit S6K, and inhibit 4E-BP1, whereby such functionalities correlates with its tumor suppressor function (pg 648, col. 2).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 2-3, GenBank NG_005895 evidence that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a hamartin binding region that is 100% identical to the amino acid sequence SEQ ID NO: 2.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding hamartin binding region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
Lo et al disclosed human TSC2 polypeptide amino acid sequence ([0043], SEQ ID NO:3), which comprises an amino acid sequence that is 100% identical to the hamartin binding region of SEQ ID NO:2.
With respect to Claims 4-5, GenBank NG_005895 evidence that those of ordinary skill in the art had long-recognized the nucleotide sequence of the human TSC2 (tuberin) gene, and the thus-encoded amino acid sequence of human TSC2 polypeptide(s), whereby said human TSC2 (tuberin) polypeptide comprises a GTPase-activating protein (GAP) region that is 100% identical to the amino acid sequence SEQ ID NO: 3.
Thus, knowing the structure of the rat cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1422 of Inoki et al, those of ordinary skill in the art would immediately recognize the corresponding GTPase-activating protein (GAP) region amino acid sequence in the context of a human cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, and lacking an Akt phosphorylation site T1462, as presently claimed.
Lo et al disclosed human TSC2 polypeptide amino acid sequence ([0043], SEQ ID NO:3), which comprises an amino acid sequence that is 100% identical to the GAP region of SEQ ID NO:3.
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Guvakova et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region (Figure 4, expression constructs), expressed in human cells (e.g. pg 190, Methods, Cells), and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Nellist et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region (pg 60, col. 1, expression constructs), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137] and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Guvakova et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. MCF-7 cells (Figure 5, legend).
Nellist et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. mouse embryo fibroblast cells (Figure 4d, legend).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Guvakova et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Nellist et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
With respect to Claim 23, Lo et al disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract), said rAAV comprising an AAV capsid and AAV genome [0026, 91-92].
With respect to Claim 30, Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
With respect to Claim 35, Lo et al disclosed wherein said patient has a renal angiomyolipoma [0017].
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
13. Claims 12-14 and 21-23 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank (NG_005895; January 31, 2016; of record) and Guvakova et al (2009; of record), Nellist et al (2005; of record), and Lo et al (U.S. 2012/0252877; of record), as applied to Claims 1-7, 10, 12-14, 18, 21-23, 30-31, and 35 above, and in further view of Ward et al (2011; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Inoki et al, Guvakova et al, Nellist et al, nor Lo et al teach/disclose ipsis verbis wherein the nucleic acid encoding TSC2 is codon-optimized for expression in human cells.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 13-14, Ward et al is considered relevant prior art for having taught the codon optimization of a therapeutic transgene for expression in a human cell (Title), whereby said codon-optimized transgene is operably linked to a regulatory control sequence (Figure 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a nucleic acid encoding a therapeutic TSC2 (syn. Tuberin) polypeptide to be codon-optimized for expression in human cells with a reasonable expectation of success, the artisan being motivated to do so because the scientific and technical concept(s) of codon-optimization has long-been recognized by the ordinary artisan, and Ward et al successfully demonstrated the ability to codon-optimize a therapeutic transgene for expression in human cells, whereby said codon-optimization “leads to high-level expression” (Title).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Guvakova et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region (Figure 4, expression constructs), expressed in human cells (e.g. pg 190, Methods, Cells), and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Nellist et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region (pg 60, col. 1, expression constructs), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137] and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
Ward et al taught the codon optimization of a therapeutic transgene for expression in a human cell (Title), whereby said codon-optimized transgene is operably linked to a regulatory control sequence (Figure 1).
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Guvakova et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. MCF-7 cells (Figure 5, legend).
Nellist et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. mouse embryo fibroblast cells (Figure 4d, legend).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Guvakova et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Nellist et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
With respect to Claim 23, Lo et al disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract), said rAAV comprising an AAV capsid and AAV genome [0026, 91-92].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector, be it lentiviral vector or rAAV viral vector (e.g. Figure 1; pg 806, col. 1).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
14. Claims 8, 12, 14, and 21-22 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank (NG_005895; January 31, 2016; of record) and Guvakova et al (2009; of record), Nellist et al (2005; of record), Lo et al (U.S. 2012/0252877; of record), and Ward et al (2011; of record), as applied to Claims 1-7, 10, 12-14, 18, 21-23, 30-31, 35, and 49 above, and in further view of Yokoi et al (U.S. Patent 6,884,419; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
As discussed supra, the instant specification fails to define a “spacer”. Inoki et al taught the rat cTuberin polypeptide naturally comprises a ‘spacer’ domain between the hamartin binding region and GAP region (Figure 4a).
Neither Inoki et al, Guvakova et al, Nellist et al, Lo et al, nor Ward et al teach/disclose wherein said spacer comprises at least SGGG, more specifically, said spacer is SEQ ID NO: 4.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 8, Yokoi et al is considered relevant prior art for having disclosed the use of spacer linkers when constructing a fusion protein, said spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 (Table 4; (SGGG)4).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first spacer domain in a cTuberin polypeptide with a second spacer domain, to wit, spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 ((SGGG)4)) with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first spacer domain in a cTuberin polypeptide with a second spacer domain, to wit, spacer linkers having the amino acid sequence of instantly recited SEQ ID NO:4 ((SGGG)4)) because those of ordinary skill in the art previously recognized the scientific and technical concepts of using compact spacer motifs, including (SGGG)4, as disclosed by Yokoi et al, in the construction of synthetic polypeptides, wherein said spacer motif allows/does not inhibit the activities of the first and second polypeptide domains linked together by said spacer motif (Yokoi et al, col. 4, lines 52-54), whereby (SGGG)4 spacer was previously recognized in the art to ensure sufficient spacing for proper peptide structure of each active domain upon expression.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 12-14, Inoki et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions (pg 651, col’s 1-2), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Guvakova et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region (Figure 4, expression constructs), expressed in human cells (e.g. pg 190, Methods, Cells), and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Nellist et al taught a nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region (pg 60, col. 1, expression constructs), and thus, said nucleic acid molecule is necessarily operably linked to a regulatory control sequence.
Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is to be expressed in a human cell, e.g. human subject [0026, 121, 137] and thus is considered to reasonably fulfill “codon-optimized for expression in a human cell”, recited at a high level of generality. Lo et al disclosed the nucleic acid encoding the TSC2 polypeptide is operably linked to a regulatory control sequence, e.g. promoter [0014].
Ward et al taught the codon optimization of a therapeutic transgene for expression in a human cell (Title), whereby said codon-optimized transgene is operably linked to a regulatory control sequence (Figure 1).
Yokoi et al disclosed a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 1).
With respect to Claim 21, Inoki et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) (pg 656, Materials and Methods), e.g. as per the molecular cloning and expression of the alanine substitutions, e.g. E. coli cells and/or HEK293 cells (entire paper).
Guvakova et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising a hamartin binding region and/or a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. MCF-7 cells (Figure 5, legend).
Nellist et al taught a cell comprising the nucleic acid molecule encoding the cTuberin polypeptide comprising at least a portion of a hamartin binding region and a GTPase-activating protein (GAP) region, e.g. as per the molecular cloning and expression of the cTuberin mutants, e.g. mouse embryo fibroblast cells (Figure 4d, legend).
Lo et al disclosed host cells transfected/transduced with the therapeutic transgene (Example 2).
Lo et al is considered relevant prior art for having disclosed rAAV (viral) vector comprising a nucleic acid encoding a TSC2 polypeptide, or variant thereof (Abstract).
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
Yokoi et al disclosed animal cells transduced or transfected with a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 2).
With respect to Claim 22, Inoki et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Guvakova et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Nellist et al taught a composition comprising the nucleic acid molecule, as such would have been immediately recognized by the ordinary artisan to have been necessarily used in order to transfect the host cells comprising said nucleic acid molecule.
Lo et al disclosed pharmaceutical composition comprising the rAAV vector and a pharmaceutically acceptable carrier [0109-110, 136].
Ward et al taught a nucleic acid molecule encoding the therapeutic polypeptide (Title), said codon-optimized nucleic acid being transduced into host cells, e.g. 293T cells (pg 800, Methods, col. 2), as well as in a viral vector (pg 799, col. 2, Methods, FVIII transgene and LV construction).
Yokoi et al disclosed animal cells transduced or transfected with a nucleic acid molecule encoding the therapeutic fusion polypeptide (Example 2).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
15. Claim(s) 48 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Inoki et al (2002; of record) in view of GenBank (NG_005895; January 31, 2016; of record) and Guvakova et al (2009; of record), Nellist et al (2005; of record), Lo et al (U.S. 2012/0252877; of record), Ward et al (2011; of record), and Yokoi et al (U.S. Patent 6,884,419; of record), as applied to Claims 1-8, 10, 12-14, 18, 21-23, 30-31, and 35, above, and in further view of Babchia et al (2010; of record) and Ji et al (published online February 11, 2017; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Inoki et al taught that Akt inhibitor LY294002 decreases the phosphorylation of Tuberin at the same Akt phosphorylation sites studied by Inoki et al (pg 651, col. 1). Thus, the ordinary artisan would have recognized the cTuberin polypeptide comprising Akt mutations, not phosphorylated by Akt, and thus a functional inhibitor of Akt, are functionally the same as wildtype TSC2 (Tuberin) in its abilities to complex with TSC1, inhibit S6K, and inhibit 4E-BP1, whereby such functionalities correlates with its tumor suppressor function (pg 648, col. 2).
Neither Inoki et al, Lo et al, Ward, nor Yokoi et al teach/disclose wherein the method of treating TSC comprises administration of rapamycin.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 48, Babchia et al is considered relevant prior art for having taught a method of treating cancer cells comprising the step of inhibiting Akt (via Ly294002) in combination with the step of inhibiting mTOR (via rapamycin), whereby the combination of the Akt inhibitor and the mTOR inhibitor yields a greater (synergistic) inhibition of cell proliferation than either Akt inhibitor or the mTOR inhibitor individually (e.g. Figure 3c; pg 425, col. 2, “synergistic effects”).
Ji et al is considered relevant prior art for having taught a method of treating TSC, the method comprising the step of inhibiting Akt (via MK-2206) in combination with the step of inhibiting mTOR (via rapamycin), whereby the Akt inhibitor increased cytotoxicity of rapamycin (Abstract) and a synergistic effect (pg 556, col. 1, “synergistic effect was detected”).
Both Babchia et al and Ji et al taught that rapamycin treatment alone activates Akt (Babchia et al, pg 421, col. 1, Results; Ji et al, pg 561, col. 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to combine a cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) with rapamycin in a method of treating TSC with a reasonable expectation of success because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. An artisan would be motivated to combine a cTuberin polypeptide comprising a hamartin binding region and a GTPase-activating protein (GAP) region, but lacking an Akt phosphorylation site(s) with rapamycin in a method of treating TSC because the ordinary artisan would have recognized the scientific and technical concepts that:
i) rapamycin treatment alone activates Akt (Babchia et al, pg 421, col. 1, Results; Ji et al, pg 561, col. 2);
ii) rapamycin treatment had been previously anticipated to be effective in the treatment of TSC, but in practice has only demonstrated modest clinical efficacy (Ji et al, pg 556, col. 1);
iii) the cTuberin polypeptide comprising Akt mutations is not phosphorylated by Akt, and thus is a functional inhibitor of Akt (Inoki et al); and
iv) both Babchia et al and Ji et al successfully demonstrated therapeutic methods, including in a method of treating TSC (Ji et al), using an Akt inhibitor in combination with a mTOR inhibitor (rapamycin), whereby the combination yielded a synergistic improvement and/or decreased rapamycin cytotoxicity (Babchia et al, Ji et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, absent evidence to the contrary, the invention as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
16. Claims 1-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,958,887. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim interpretation: ‘887 recites the limitation “lacks amino acids 451-1514 of human tuberin (SEQ ID NO:10).
Claim 6 of instant application also recites the limitation “lacks amino acids 451-1514 of human tuberin (SEQ ID NO:10).
As discussed in prosecution of parent application 16/613,907, Examiner’s statement for reasons of allowance, paper mailed December 14, 2023, the claims are directed to an internally deleted Tuberin protein (e.g. ‘887, col. 8, lines 54-55, “our condensed form of tuberin was accomplished by deleting the central portion of the human tuberin cDNA”; Figure 2A, “internally deleted Tuberin (syn. condensed Tuberin; cTuberin)).
‘887 claims a cTuberin polypeptide comprising:
a) a hamartin binding region at least 94% identical to SEQ ID NO:2;
b) a GTPas-activating protein (GAP) region at least 93% identical to SEQ ID NO:3; and
c) lacking an Akt phosphorylation site Thr 1462, as it lacks amino acids 451-1514 of SEQ ID NO:10.
More specifically, ‘887 claims wherein the cTuberin polypeptide has the amino acid sequence of SEQ ID NO:1.
Thus, instant claims are considered to be anticipated by and/or obvious variants of the’887 patented claims.
Conclusion
17. Claims 1-8, 10, 12-14, 18, 21-23, 30-31, 35, and 48 are rejected.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights