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 April 28, 2026.
Amendments
Applicant's amendments, filed April 28, 2026, are acknowledged. Applicant has cancelled Claims 8-9 and 15-16, and amended Claims 1 and 5.
Claims 1-7, 10-14, and 17-24 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group III, claim(s) 1-7 and 10-14, drawn to a method of delivering to a subject a transgene comprising:
a) the nucleotide sequence of SEQ ID NO:1, 6, 7, 8, or 9, or at least 90% identity to SEQ ID NO:1, 6, 7, 8, or 9, encoding a Neurofibromatosis type 2 (NF2)/Merlin protein; or
b) the nucleotide sequence of SEQ ID NO:16, 17, 18, 19, or 20, or at least 90% identity to SEQ ID NO: 16, 17, 18, 19, or 20, encoding a phosphorylation-resistant Neurofibromatosis type 2 (NF2)/Merlin protein with tumor suppressor activity.
Within Group III, Applicant has elected without traverse the following species, wherein:
i) the alternative transgene SEQ ID NO is SEQ ID NO:6 (400bp promoter and NF2 isoform 1 cDNA), as recited in Claim 1;
ii) the alternative rAAV serotype is AAV9, as recited in Claim 10; and
iii) the alternative delivery route is intrathecal delivery, as recited in Claims 1-2 and 11-14.
Claims 1-7, 10-14, and 17-24 are pending.
Claims 13-14 and 17-24 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-7 and 10-12 are under consideration.
Priority
This application is a 371 of PCT/US2022/24680 filed on April 13, 2022. Applicant’s claim for the benefit of a prior-filed application provisional application 63/174,803 filed on April 14, 2021 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 Information Disclosure Statements on January 10, 2024, July 8, 2025, and April 1, 2026 that have been considered.
The information disclosure statement filed January 10, 2024 and July 8, 2025 fail 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.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
1. The prior objection to the disclosure is withdrawn in light of Applicant’s amendment, which the Examiner finds persuasive.
Claim Objections
2. The prior objection to Claim 1 is withdrawn in light of Applicant’s amendment to the claim to separate the elements by line indentation, which the Examiner finds persuasive.
3. Claim 2 is objected to because of the following informalities: the claim is unnecessarily verbose.
Claim 1 recites the step of administering the gene therapy vector by intravenous, intratumoral, or intrathecal delivery.
Thus, recitation of this step in Claim 2 (lines 2-4) ‘wherein’ clause is redundant to that which has already been recited in the independent claim.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
4. Claims 3-7 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites a method of delivering a transgene encoding a Merlin protein with tumor suppressor activity to a subject in need of Merlin protein tumor suppressor activity, the method comprising the step(s) of administering by intrathecal delivery to said subject a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6.
Claim 2 recites wherein the subject has at least one defective NF2 allele.
Claim 3 recites wherein the transgene is delivered to Schwann cells, Meningeal cells, or both, of the subject.
Claim 4 recites wherein the administration treats a malignant glioblastoma in the subject.
Claim 5 recites wherein the administration treats NF2 in the subject.
Claim 6 recites wherein the [intrathecal] administration alleviates one or more of tumors, hearing loss, tinnitus, balance problems, facial weakness or numbness, visual impairment, cataract, seizure and brainstem compression in the subject.
Claim 7 recites wherein the tumors are one or more of schwannomas, meningiomas, ependymomas, or other cranial nerve tumors.
Either the results recited in Claims 3-7 are, concordantly and respectively, inherent properties of (that naturally flow from) the structure (a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6) and/or method step of intrathecal administration of Claims 1-2, or they are not, and something structural and/or method step of independent Claim 1 must change.
See further discussion below in the 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
To the extent they are, concordantly and respectively, inherent properties of (that naturally flow from) the method of Claims 1-2, then the instant claims fail to further limit Claims 1 and/or 2.
Furthermore, in regard to instant claims, it is noted that the “wherein” clauses do not recite any additional structure and/or method step, concordantly and respectively, but simply states a characterization or conclusion of the results of method recited in Claims 1-2. Therefore, the "wherein" clauses are not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
5. Claim(s) 1-12 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.
Claim 1 recites a method of delivering a transgene encoding a Merlin protein with tumor suppressor activity to a subject in need of Merlin protein tumor suppressor activity, the method comprising the step(s) of administering by intrathecal delivery to said subject a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6.
The claim denotes that there is a first population of human and non-human animal subjects who are not “in need of Merlin protein tumor suppressor activity”, as opposed to a second population of human and non-human animal subjects who are “in need of Merlin protein tumor suppressor activity”.
Claim 2 recites wherein the subject has at least one defective NF2 allele.
Claim 3 recites wherein the transgene is delivered to Schwann cells, Meningeal cells, or both, of the subject.
Claim 4 recites wherein the administration treats a malignant glioblastoma in the subject.
Claim 5 recites wherein the administration treats NF2 in the subject.
Claim 6 recites wherein the [intrathecal] administration alleviates one or more of tumors, hearing loss, tinnitus, balance problems, facial weakness or numbness, visual impairment, cataract, seizure and brainstem compression in the subject.
Claim 7 recites wherein the tumors are one or more of schwannomas, meningiomas, ependymomas, or other cranial nerve tumors.
Either the results recited in Claims 3-7 are, concordantly and respectively, inherent properties of (that naturally flow from) the structure (a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6) and/or method step of intrathecal administration of Claims 1-2, or they are not, and something structural and/or method step of independent Claim 1 must change.
The Examiner incorporates herein the above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent they are, concordantly and respectively, not inherent properties of (that naturally flow from) the method of Claims 1-2, then something must change in order to necessarily and predictably achieve each of the recited functional limitations/phenotypic results, concordantly and respectively, recited in dependent Claims 3-7.
The claims are considered indefinite for failing to recite the necessary structure/function nexus and/or method step/function nexus that is/are necessary and sufficient to cause the recited functional language.
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 human or non-human animal to be treated [parameter 1];
the genus of NF2 promoter variants encoded by SEQ ID NO:6, or at least 90% identical thereto [parameter 2];
the genus of Merlin protein variants tumor suppressor activity encoded by the nucleic acid SEQ ID NO:6, or at least 90% identical thereto [parameter 3], operably linked to the [parameter 2] NF2 promoter variants;
the genus of gene therapy vectors, recited at a high level of generality [parameter 4] comprising the [parameter 2, parameter 3] transgene of SEQ ID NO:6, or at least 90% identical thereto;
the dosage administered [parameter 5];
the administration route [parameter 6];
the disease/disorder/condition to be treated [parameter 7]; and
the phenotypic response to be achieved [parameter 8].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the gene therapy vector comprising the transgene of SEQ ID NO:6, or at least 90% identical thereto, that, upon intrathecal administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are broad for reciting the subject in need of a Merlin protein tumor suppressor activity, including those subjects having at least one defective NF2 allele, at a high level of generality.
The specification discloses the subject may be a human or non-human animal (e.g. [0063], “humans and other animals”; [0097], “subject (e.g. an animal, including, but not limited to, a human patient)”).
Thus, the breadth of the claims reasonably encompasses an enormous genus of 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).
The claim denotes that there is a first population of human and non-human animal subjects who are not “in need of Merlin protein tumor suppressor activity”, as opposed to a second population of human and non-human animal subjects who are “in need of Merlin protein tumor suppressor activity”.
The determination of whether or not an individual of the about 1x10^6 human and non-human animal subjects is or is not “in need of Merlin protein tumor suppressor activity” is considered an arbitrary and subjective determination.
The claims fail to recite, and the specification fails to disclose, a first subject of the about 1x10^6 human and non-human animal subjects, who is objectively not “in need of Merlin protein tumor suppressor activity”, as opposed to a second subject of the about 1x10^6 human and non-human animal subjects, who is objectively “in need of Merlin protein tumor suppressor activity”, for example.
The Examiner suggests cancellation of the phrase “in need of Merlin protein tumor suppressor activity”.
Parameter 2
Claim 1 recites a gene therapy vector comprising the polynucleotide of SEQ ID NO:6 (2483 nucleotides), or at least 90% identity thereto, which allows for as many as 248 nucleotide insertions, deletions, and/or substitutions distributed anywhere in SEQ ID NO:6.
Nucleotides 1-400 of SEQ ID NO:6 are disclosed to encode a NF2 promoter.
Nucleotides 413-512 of SEQ ID NO:6 are disclosed to encode an SV40 intron.
Nucleotides 530-2417 of SEQ ID NO:6 are disclosed to encode a NF2 cDNA.
Nucleotides 2435-2483 of SEQ ID NO:6 are disclosed to encode a polyA sequence.
Thus, the breadth of the claims reasonably encompasses as many as 248 nucleotides in the NF2 promoter that are modified, resulting in only about 62% identity to nucleotides 1-400.
4^248 = about 2x10^149 structurally and functionally undisclosed NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6.
Even if one were to limit the genus of NF2 promoter variants to be at least 90% identical to nucleotides 1-400 of SEQ ID NO:6, such allows for as many as 40 nucleotide insertions, deletions, and/or substitutions.
4^40 = about 1x10^24 structurally and functionally undisclosed variants of nucleotides 1-400 of SEQ ID NO:6.
(calculator.net/exponent-calculator; last visited May 11, 2026)
The breadth of the claims reasonably encompasses as many as 248 nucleotide insertions, deletions, and/or substitutions anywhere in SEQ ID NO:6.
Thus, the breadth of the independent claim is such that the SV40 intron (99 nucleotides) of instant SEQ ID NO:6 need not even be present, while also allowing as many as 149 nucleotide insertions, deletions, and/or substitutions distributed elsewhere in SEQ ID NO:6, e.g. the NF2 promoter and/or the NF2 cDNA, for example.
Parameter 3
Claim 1 recites a gene therapy vector comprising the polynucleotide of SEQ ID NO:6 (2483 nucleotides), or at least 90% identity thereto, which allows for as many as 248 nucleotide insertions, deletions, and/or substitutions distributed anywhere in SEQ ID NO:6.
Thus, the breadth of the claims reasonably encompasses as many as 248 nucleotides in the NF2 cDNA that are modified, resulting in only about 87% identity to nucleotides 530-2417.
4^248 = about 2x10^149 structurally and functionally undisclosed NF2 cDNA variants of nucleotides 530-2417 of SEQ ID NO:6.
Even if one were to limit the genus of NF2 cDNA variants to be at least 90% identical to nucleotides 530-2417 of SEQ ID NO:6, encoding Merlin protein variants having tumor suppressor activity, such allows for as many as 189 nucleotide insertions, deletions, and/or substitutions.
4^189 = about 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6.
The specification discloses the Merlin protein variant may be resistant to post-translational negative regulation, such as phosphorylation (e.g. [0073]).
The specification discloses the Merlin protein may have an amino acid sequence that is at least 90% identical to SEQ ID NO:15 (595 amino acids) (e.g. [0070]).
90% identity allows for as many as 60 amino acid insertions, deletions, and/or substitutions.
20^60 = about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15.
Parameter 4
The claimed methods are recited at a high level of generality for type of nucleic acid vector to be administered, said vectors including, but not limited to RNA molecules, plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles.
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 5
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 6
The claims recite the gene therapy vector is administered to the subject via intrathecal delivery.
Parameter 7
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions “in need of Merlin protein tumor suppressor activity”, including, but not limited to cancer (e.g. genus recited in [0093]), degenerative nerve diseases, neurodegeneration, vision impairment, hearing loss, balance problems, facial paralysis, seizure, and brainstem compression (e.g. [0005]).
Parameter 8
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 gene therapy vector expressing the Merlin protein having tumor suppressor activity must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
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 comprising the gene therapy vector comprising the transgene of SEQ ID NO:6, or at least 90% identical thereto, that, upon intrathecal administration to the subject, is not, in fact, “a therapeutically effective amount”.
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 “[T]here is no cure for NF2” (e.g. [0006]).
The specification discloses, for example:
i) alleviates, reduces, or eliminates at least one symptom associated with the condition (e.g. [0097]), which itself is an arbitrary and subjective determination;
ii) slows or prevents progression of the condition (e.g. [0097]);
iii) diminishes or results in partial or total remission of the condition (e.g. [0097]);
iv) prolongs survival (e.g. [0097]);
v) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas (e.g. [0098]);
vi) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas (e.g. [0098]);
vii) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas (e.g. [0098]);
viii) reduces the size and/or number of tumors (e.g. [0099]);
ix) reduces the formation of metastases (e.g. [0099]);
x) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression (e.g. [0099]); and/or
xi) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2 (e.g. [0099]).
The claims fail to recite, and the specification fails to disclose, a first gene therapy vector [parameter 4], e.g. bacteriophage, encoding a first NF2 promoter variant [parameter 2] of the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed variants of nucleotides 1-400 of SEQ ID NO:6 operably linked to a first Merlin protein variant [parameter 3] of the enormously vast genus of about 2x10^149 and/or 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 encoded by the enormously vast genus of about 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6, and its corresponding dosage [parameter 5], that upon intrathecal administration to a first animal subject in need of Merlin protein tumor suppressor activity of the enormous genus of about 1x10^6 animal subjects [parameter 1], e.g. a chicken, will necessarily and predictably achieve elimination [parameter 8] of hearing loss [parameter 7], for example.
The claims fail to recite, and the specification fails to disclose, a second gene therapy vector [parameter 4], e.g. cosmid, encoding a first NF2 promoter variant [parameter 2] of the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed variants of nucleotides 1-400 of SEQ ID NO:6 operably linked to a first Merlin protein variant [parameter 3] of the enormously vast genus of about 2x10^149 and/or 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 encoded by the enormously vast genus of about 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6, and its corresponding dosage [parameter 5], that upon intrathecal administration to a second animal subject in need of Merlin protein tumor suppressor activity of the enormous genus of about 1x10^6 animal subjects [parameter 1], e.g. a horse, will necessarily and predictably achieve elimination [parameter 8] of balance problems [parameter 7], for example.
If there are multiple ways to measure “therapeutically effective dose”, to wit, structure and function of the Merlin protein variants encoded by the genus of nucleic acid variants of SEQ ID NO:6, structure and function of the NF2 promoter variants encoded by the genus of nucleic acid variants of SEQ ID NO:6, genus of gene therapy vector variants, genus of unrecited doses of said genus of gene therapy vector variants to be administered to the genus of about 1x10^6 different human and non-human animal subjects, 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 gene therapy vector dosage administered 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.
Appropriate correction is required.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
6. Claim(s) 1-12 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 incorporates herein the above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
Claim 1 recites a method of delivering a transgene encoding a Merlin protein with tumor suppressor activity to a subject in need of Merlin protein tumor suppressor activity, the method comprising the step(s) of administering by intrathecal delivery to said subject a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6.
The claim denotes that there is a first population of human and non-human animal subjects who are not “in need of Merlin protein tumor suppressor activity”, as opposed to a second population of human and non-human animal subjects who are “in need of Merlin protein tumor suppressor activity”.
Claim 2 recites wherein the subject has at least one defective NF2 allele.
Claim 3 recites wherein the transgene is delivered to Schwann cells, Meningeal cells, or both, of the subject.
Claim 4 recites wherein the administration treats a malignant glioblastoma in the subject.
Claim 5 recites wherein the administration treats NF2 in the subject.
Claim 6 recites wherein the [intrathecal] administration alleviates one or more of tumors, hearing loss, tinnitus, balance problems, facial weakness or numbness, visual impairment, cataract, seizure and brainstem compression in the subject.
Claim 7 recites wherein the tumors are one or more of schwannomas, meningiomas, ependymomas, or other cranial nerve tumors.
Either the results recited in Claims 3-7 are, concordantly and respectively, inherent properties of (that naturally flow from) the structure (a gene therapy vector comprising a transgene comprising the polynucleotide of SEQ ID NO:6, or a polynucleotide at least 90% identical to SEQ ID NO:6) and/or method step of intrathecal administration of Claims 1-2, or they are not, and something structural and/or method step of independent Claim 1 must change.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent they are, concordantly and respectively, not inherent properties of (that naturally flow from) the method of Claims 1-2, then something must change in order to necessarily and predictably achieve each of the recited functional limitations/phenotypic results, concordantly and respectively, recited in dependent Claims 3-7.
The claims are considered lack adequate written description for failing to recite the necessary structure/function nexus and/or method step/function nexus that is/are necessary and sufficient to cause the recited functional language.
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).
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 human or non-human animal to be treated [parameter 1];
the genus of NF2 promoter variants encoded by SEQ ID NO:6, or at least 90% identical thereto [parameter 2];
the genus of Merlin protein variants tumor suppressor activity encoded by the nucleic acid SEQ ID NO:6, or at least 90% identical thereto [parameter 3], operably linked to the [parameter 2] NF2 promoter variants;
the genus of gene therapy vectors, recited at a high level of generality [parameter 4] comprising the [parameter 2, parameter 3] transgene of SEQ ID NO:6, or at least 90% identical thereto;
the dosage administered [parameter 5];
the administration route [parameter 6];
the disease/disorder/condition to be treated [parameter 7]; and
the phenotypic response to be achieved [parameter 8].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the gene therapy vector comprising the transgene of SEQ ID NO:6, or at least 90% identical thereto, that, upon intrathecal administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are broad for reciting the subject in need of a Merlin protein tumor suppressor activity, including those subjects having at least one defective NF2 allele, at a high level of generality.
The specification discloses the subject may be a human or non-human animal (e.g. [0063], “humans and other animals”; [0097], “subject (e.g. an animal, including, but not limited to, a human patient)”).
Thus, the breadth of the claims reasonably encompasses an enormous genus of about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021; of record), 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; of record).
The claim denotes that there is a first population of human and non-human animal subjects who are not “in need of Merlin protein tumor suppressor activity”, as opposed to a second population of human and non-human animal subjects who are “in need of Merlin protein tumor suppressor activity”.
The determination of whether or not an individual of the about 1x10^6 human and non-human animal subjects is or is not “in need of Merlin protein tumor suppressor activity” is considered an arbitrary and subjective determination.
The working Examples disclose administering a recombinant AAV gene therapy vector to mouse subjects, including mouse subjects comprising loss-of-function NF2 alleles (e.g. Examples 2-3).
While it is clear that the NF2 mutant mice are an animal model of human disease, there is no clear objective evidence that they are necessarily “in need of Merlin protein tumor suppressor activity”, rather than, e.g. simple euthanasia per humane animal husbandry practices.
The NF2 mutant mice are not, per se, “in need of Merlin protein tumor suppressor activity” because the NF2 mutant mice are being intentionally created for research purposes, including, but not limited to, the study of the role NF2 plays in development or cancer biology.
The claims fail to recite, and the specification fails to disclose, a first subject of the about 1x10^6 human and non-human animal subjects, who is objectively not “in need of Merlin protein tumor suppressor activity”, as opposed to a second subject of the about 1x10^6 human and non-human animal subjects, who is objectively “in need of Merlin protein tumor suppressor activity”, for example.
The Examiner suggests cancellation of the phrase “in need of Merlin protein tumor suppressor activity”.
Those of ordinary skill in the art would immediately recognize that the mouse subject does not adequately describe the enormously vast genus of about 1x10^6 human and non-human animal subjects encompassed by the claims.
Parameter 2
Claim 1 recites a gene therapy vector comprising the polynucleotide of SEQ ID NO:6 (2483 nucleotides), or at least 90% identity thereto, which allows for as many as 248 nucleotide insertions, deletions, and/or substitutions distributed anywhere in SEQ ID NO:6.
Nucleotides 1-400 of SEQ ID NO:6 are disclosed to encode a NF2 promoter.
Nucleotides 413-512 of SEQ ID NO:6 are disclosed to encode an SV40 intron.
Nucleotides 530-2417 of SEQ ID NO:6 are disclosed to encode a NF2 cDNA.
Nucleotides 2435-2483 of SEQ ID NO:6 are disclosed to encode a polyA sequence.
Thus, the breadth of the claims reasonably encompasses as many as 248 nucleotides in the NF2 promoter that are modified, resulting in only about 62% identity to nucleotides 1-400.
4^248 = about 2x10^149 structurally and functionally undisclosed NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6.
Even if one were to limit the genus of NF2 promoter variants to be at least 90% identical to nucleotides 1-400 of SEQ ID NO:6, such allows for as many as 40 nucleotide insertions, deletions, and/or substitutions.
4^40 = about 1x10^24 structurally and functionally undisclosed variants of nucleotides 1-400 of SEQ ID NO:6.
(calculator.net/exponent-calculator; last visited May 11, 2026)
The breadth of the claims reasonably encompasses as many as 248 nucleotide insertions, deletions, and/or substitutions anywhere in SEQ ID NO:6.
Thus, the breadth of the independent claim is such that the SV40 intron (99 nucleotides) of instant SEQ ID NO:6 need not even be present, while also allowing as many as 149 nucleotide insertions, deletions, and/or substitutions distributed elsewhere in SEQ ID NO:6, e.g. the NF2 promoter and/or the NF2 cDNA, for example.
The specification discloses the transgene is to be expressed in, e.g. neural cells such as vestibular nuclei, sciatic nerve (e.g. [0024-28]), “specifically within” neurons, astrocytes, Schwann cells (e.g. [0075]), meningeal cells (e.g. [0092]), or cancer cells (e.g. [0093]).
However, the working Examples use only the NF2 promoter of nucleotides 1-400 of SEQ ID NO:6.
Those of ordinary skill in the art would immediately recognize that the single species of the NF2 promoter of nucleotides 1-400 of SEQ ID NO:6 does not adequately represent the enormously vast genus of about 1x10^24 structurally and functionally undisclosed variants of nucleotides 1-400 of SEQ ID NO:6 encompassed by the claims.
Blanco et al (Transcription Factor Map Alignment of Promoter Regions, PLoS Computational Biology 2(5): e49, 14 pages, DOI: 10.1371/journal.pcbi.0020049, May, 2006) is considered relevant prior art for having taught that while sequence comparisons and alignments are among the most powerful tools in research in biology, such has limitations because often similar functions are encoded by higher order elements which do not hold a univocal relationship to the underlying primary sequence. In consequence, similar functions are frequently encoded by diverse sequences. Promoter regions, which are functionally defined genetic elements, are a case in point. Often, promoter sequences of genes with similar expression patterns do not show conservation. This is because, even though their expression may be regulated by a similar arrangement of transcription factors, the binding sites for these factors may exhibit great sequence variability (e.g. pg 2, col. 1).
Heinz et al (The selection and function of cell type-specific enhancers, Nat Rev Mol Cell Biol 16, 144–154, doi.org/10.1038/nrm3949, available online February 4, 2015) is considered relevant post-filing art for having taught that enhancers, which are functionally defined genetic elements, may be located at distances ranging from hundreds to millions of nucleotides away from a given target gene (pg 144, col. 1). Beyond the simple annotation of regulatory regions in the genome, it is important to understand how cells select the full complement of enhancers that are required for maintaining their identities and functions. Defining functional enhancer–promoter interactions remains an important goal. Despite being informative, chromatin connectivity maps do not directly relate chromatin interactions to the regulation of gene expres-sion. Definitive evidence that a specific enhancer-like region exerts a transcriptional regulatory function requires the study of mutational effects on that region (e.g. pg 152, col. 2).
Maston et al (Transcriptional Regulatory Elements in the Human Genome, Ann. Rev. Genomics Hum. Genet. 7: 29-59, 2006) is considered relevant prior art for having taught that one of the main emerging challenges for genomics research is to identify all functional elements in the genome, including those that regulate gene expression (pg 30, col. 1). The structure of human gene promoters can be quite complex, typically consisting of multiple transcriptional regulatory elements. The presence of multiple regulatory elements within promoters confers combinatorial control of regulation, which exponentially increases the potential number of unique expression patterns. Such transcriptional regulatory elements include locus control regions (LCRs), insulators, silencers, enhancer, the core promoter, and proximal promoter elements (Figure 1), whereby the distal elements such as LCRs, insulators, silencers, and enhancers may well be over 1 megabase (1 million nucleotides in length) away from the promoter. These regulatory elements can be widely dispersed from the corresponding target gene each regulates (pg 42, col. 2). Identifying the promoter of a specific target gene can be a challenge because the core promoter is often distantly located from the first coding exon (pg 45, col. 1). In addition, because promoters can contain any one of a number of combinations of core promoter elements [and, conversely, many promoters have only one or no such elements (68)], simply searching for the co-occurrence of known core promoter motifs has had only limited success (pg 45, col. 2). Although much improved over earlier prediction programs, these methods still have limited sensitivity and specificity when applied to genome-scale sequence data (pg 45, col. 2). While a number of bioinformatics approaches attempt to list potential transcription factor binding sites based on a statistical match between a region in the sequence and a site matrix. This analysis is often hampered by the prediction of a large number of sites, a significant fraction of which are likely false positives. In addition to the false-positive problem, the completeness of these databases is also an issue; it is likely that not all DNA-binding transcription factors have been identified, and even for some known factors, their binding specificity has not yet been fully characterized. (pg 46, col. 2). Transcription factor binding sites are small and degenerate, are often located distantly from the promoter upon which they act, and are not always conserved through evolution. These properties make regulatory elements difficult to identify through computational means alone (pg 48, col. 2).
Similarly, Thakurta (Computational identification of transcriptional regulatory elements in DNA sequence, Nucleic Acids Res. 34(12): 3585-3598, 2006) is considered relevant prior art for having taught that identification and annotation of all the functional elements in the genome, including genes and the regulatory sequences, is a fundamental challenge in genomics and computational biology. Since regulatory elements are frequently short and variable, their identification and discovery using computational algorithms is difficult (Abstract). However, our knowledge of the transcriptional regulatory elements in the genome and their contribution to gene expression in different spatial and temporal contexts is still limited. Given the complex pattern of regulatory interactions, the challenges involved in the complete elucidation of these elements in the genome are substantial (pg 3593, Conclusion).
The specification fails to make up for the deficiencies of the global scientific community.
Thus, the breadth of the claims reasonably encompasses an enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, variants of nucleotides 1-400 of SEQ ID NO:6 genetic elements that are to have the functional property of being a promoter and/or enhancer, to thereby necessarily and predictably drive expression of the Merlin protein-encoding cDNA in the enormous genus of neural cells, such as vestibular nuclei, sciatic nerve, “specifically within” neurons, astrocytes, Schwann cells, meningeal cells, or the genus of etiologically distinct cancer cells, whereby those of ordinary skill in the art have long-recognized that the identification of such elements is predicated on a functional analysis, as similar functions are frequently encoded by diverse sequences, and the binding sites for these factors may exhibit great sequence variability.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus of enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, variants of nucleotides 1-400 of SEQ ID NO:6 genetic elements to thereby necessarily and predictably drive expression of the Merlin protein-encoding cDNA in the enormous genus of neural cells, such as vestibular nuclei, sciatic nerve, “specifically within” neurons, astrocytes, Schwann cells, meningeal cells, or the genus of etiologically distinct cancer cells.
The claims fail to recite, and the specification fails to disclose, a first NF2 promoter variant of enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, variants of nucleotides 1-400 of SEQ ID NO:6 genetic elements, that, while capable of driving expression of the Merlin protein-encoding cDNA in non-human animal cell, e.g. an insect cell, is unable to drive expression of the Merlin protein-encoding cDNA in, e.g. a mammalian meningeal cell, for example.
The claims fail to recite, and the specification fails to disclose, a first NF2 promoter variant of enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, variants of nucleotides 1-400 of SEQ ID NO:6 genetic elements, that, while capable of driving expression of the Merlin protein-encoding cDNA in non-human animal cell, e.g. an worm cell, is unable to specifically drive expression of the Merlin protein-encoding cDNA in, e.g. an astrocyte, as opposed to
a second NF2 promoter variant of enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, variants of nucleotides 1-400 of SEQ ID NO:6 genetic elements, that, while capable of driving expression of the Merlin protein-encoding cDNA in a cancer cell, e.g. leukemia, is unable to specifically drive expression of the Merlin protein-encoding cDNA in, e.g. a human vestibular neuron, for example.
Parameter 3
Claim 1 recites a gene therapy vector comprising the polynucleotide of SEQ ID NO:6 (2483 nucleotides), or at least 90% identity thereto, which allows for as many as 248 nucleotide insertions, deletions, and/or substitutions distributed anywhere in SEQ ID NO:6.
Thus, the breadth of the claims reasonably encompasses as many as 248 nucleotides in the NF2 cDNA that are modified, resulting in only about 87% identity to nucleotides 530-2417.
4^248 = about 2x10^149 structurally and functionally undisclosed NF2 cDNA variants of nucleotides 530-2417 of SEQ ID NO:6.
Even if one were to limit the genus of NF2 cDNA variants to be at least 90% identical to nucleotides 530-2417 of SEQ ID NO:6, encoding Merlin protein variants having tumor suppressor activity, such allows for as many as 189 nucleotide insertions, deletions, and/or substitutions.
4^189 = about 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6.
The specification discloses the Merlin protein variant may be resistant to post-translational negative regulation, such as phosphorylation (e.g. [0073]).
The specification discloses the Merlin protein may have an amino acid sequence that is at least 90% identical to SEQ ID NO:15 (595 amino acids) (e.g. [0070]).
90% identity allows for as many as 60 amino acid insertions, deletions, and/or substitutions.
20^60 = about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15.
However, the working Examples use only the Merlin amino acid sequence of SEQ ID NO:15.
Those of ordinary skill in the art would immediately recognize that the single species of the Merlin amino acid sequence of SEQ ID NO:15 does not adequately represent the enormously vast genus of about 2x10^149 and/or 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 and/or the enormously vast genus of structurally and functionally undisclosed Merlin protein variants encoded by the enormously vast genus of about 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 encompassed by the claims.
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 Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 will necessarily and predictably have the recited functional property(ies) of:
i) alleviates, reduces, or eliminates at least one symptom associated with the condition;
ii) slows or prevents progression of the condition;
iii) diminishes or results in partial or total remission of the condition;
iv) prolongs survival;
v) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
vi) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
vii) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
viii) reduces the size and/or number of tumors;
ix) reduces the formation of metastases;
x) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
xi) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2,
as recited in Claims 3-7 and/or as disclosed in the specification (e.g. [0097-99]).
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 enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 variants, 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.
The claims fail to recite, and the specification fails to disclose, a first Merlin protein variant of the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15, that while able to alleviate at least one symptom associated with a condition, is unable to reduce metastases formation, as opposed a second Merlin protein variant of the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15, that is necessarily and predictably able to eliminate hearing loss, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first Merlin protein variant of the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15, that is unable to eliminate glioblastoma, into a second Merlin protein variant that now is necessarily and predictably able to result in total remission of schwannomas, meningiomas, and/or glioblastomas, for example.
Parameter 4
The claimed methods are recited at a high level of generality for type of nucleic acid vector to be administered, said vectors including, but not limited to RNA molecules, plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles.
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; of record).
The specification working Examples are directed to scAAV9 expression vectors (e.g. Example 1).
Those of ordinary skill in the art would immediately recognize that the single species of scAAV9 expression vectors does not adequately represent vectors including, but not limited to RNA molecules, plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles encompassed by the claims.
Parameter 5
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]; of record).
The specification working Examples are directed to administration of about 1x10^11 or about 5x10^11 scAAV9 vector genomes to a mouse subject (e.g. Examples 2-3).
Those of ordinary skill in the art would immediately recognize that the single species of about 1x10^11 or about 5x10^11 scAAV9 vector genomes does not adequately represent the enormously broad genus of as little as 1x10^2 to 1x10^20 vector genomes, of the broadly claimed genus of vectors including, but not limited to RNA molecules, plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles encompassed by the claims.
Parameter 6
The claims recite the gene therapy vector is administered to the subject via intrathecal delivery.
Parameters 7-8
While Claim 1 method of delivering does not recite ipsis verbis that the gene therapy vector treats the subject, it is understood that gene therapy vectors are, by design, therapeutic, and 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 gene therapy vector expressing the Merlin protein having tumor suppressor activity must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
Utilities that require or constitute carrying out further research to identify or reasonably confirm a real world context of use are not substantial utilities. Research that involves studying the properties of the claimed product itself does not constitute a substantial utility. See also MPEP 2107-2107.02, and Brenner Comr. Pats. v. Manson, 148 USPQ 689 (US SupCt 1966).
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions “in need of Merlin protein tumor suppressor activity”, including, but not limited to cancer (e.g. genus recited in [0093]), degenerative nerve diseases, neurodegeneration, vision impairment, hearing loss, balance problems, facial paralysis, seizure, and brainstem compression (e.g. [0005]).
The specification discloses “[T]here is no cure for NF2” (e.g. [0006]).
The claims fail to recite, and the specification fails to disclose, a nexus between:
i) the broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) the enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) the broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], will necessarily and predictably achieve a real-world, and clinically meaningful therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2;
v) in the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1] encompassed by the claims.
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”).
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 gene therapy vector is a scAAV9 expression vector whose genome comprises the nucleotide sequence of SEQ ID NO:6, encoding the Merlin protein amino acid sequence of SEQ ID N:15,
does not tell you anything at all about:
i) the broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) the enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) the broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], will necessarily and predictably achieve a real-world, and clinically meaningful therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2;
v) in the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1] encompassed by the claims.
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 Applicant seeks to claim for themselves:
i) a broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) an enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) an enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) a broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], to;
v) the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1], so as to achieve a therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2.
“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 working examples (Examples 2-3) are directed to administering about 1x10^11 or about 5x10^11 scAAV9 vector genomes to a mouse subject.
Instant claims are vastly broader in scope than the actual invention.
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 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).
7. Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabling for a method of delivering by intrathecal injection to a mouse subject a self-complementary AAV9 vector whose genome comprises the nucleotide sequence of SEQ ID NO:6, does not reasonably provide enablement for:
i) the broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) the enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) the broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], will necessarily and predictably achieve a real-world, and clinically meaningful therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2;
v) in the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1] encompassed by the claims.
The Examiner incorporates herein the above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
While Claim 1 method of delivering does not recite ipsis verbis that the gene therapy vector treats the subject, it is understood that gene therapy vectors are, by design, therapeutic, and 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 gene therapy vector expressing the Merlin protein having tumor suppressor activity must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
Utilities that require or constitute carrying out further research to identify or reasonably confirm a real world context of use are not substantial utilities. Research that involves studying the properties of the claimed product itself does not constitute a substantial utility. See also MPEP 2107-2107.02, and Brenner Comr. Pats. v. Manson, 148 USPQ 689 (US SupCt 1966).
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”.
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 gene therapy vector is a scAAV9 expression vector whose genome comprises the nucleotide sequence of SEQ ID NO:6, encoding the Merlin protein amino acid sequence of SEQ ID N:15,
does not tell you anything at all about:
i) the broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) the enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) the broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], will necessarily and predictably achieve a real-world, and clinically meaningful therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2;
v) in the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1] encompassed by the claims.
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 Applicant seeks to claim for themselves:
i) a broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) an enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) an enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) a broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5], to;
v) the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1], so as to achieve a therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2.
“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 working examples (Examples 2-3) are directed to administering about 1x10^11 or about 5x10^11 scAAV9 vector genomes to a mouse subject.
Instant claims are vastly broader in scope than the actual invention.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
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 formulate a pharmaceutical composition comprising:
i) the broadly claimed genus of gene therapy vectors recited at a high level of generality [parameter 4] encoding;
ii) the enormously vast genus of about 2x10^149 and/or 1x10^24 structurally and functionally undisclosed, and yet-to-be identified, NF2 promoter variants of nucleotides 1-400 of SEQ ID NO:6 [parameter 2] operably linked to;
iii) the enormously vast genus of Merlin protein variants encoded by the polynucleotides of the enormously vast genus of about 2x10^149 and/or 6x10^113 structurally and functionally undisclosed variants of nucleotides 530-2417 of SEQ ID NO:6 and/or the enormously vast genus of about 1x10^78 structurally and functionally undisclosed Merlin protein variants of SEQ ID NO:15 [parameter 3], that, upon intrathecal administration at;
iv) the broad genus of gene therapy vector doses, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more [parameter 5];
so as to necessarily and predictably achieve a real-world, and clinically meaningful therapeutic result [parameters 7-8], including, but not limited to:
a) alleviates, reduces, or eliminates at least one symptom associated with the condition;
b) slows or prevents progression of the condition;
c) diminishes or results in partial or total remission of the condition;
d) prolongs survival;
e) alleviates, reduces, or eliminates at least one symptom associated with schwannomas, meningiomas, and/or glioblastomas;
f) slows or prevents progression of schwannomas, meningiomas, and/or glioblastomas;
g) diminishes or results in partial or total remission of schwannomas, meningiomas, and/or glioblastomas;
h) reduces the size and/or number of tumors;
i) reduces the formation of metastases;
j) alleviates, reduces, or eliminates at least one symptom associated with hearing loss, tinnitus (ringing ears), balance problems, facial weakness or numbness, visual impairment, cataract, seizure, and brainstem compression; and/or
k) slows or prevents progression of NF2, that diminishes the extent of NF2, that results in remission (partial or total) of NF2; in
v) the enormously vast genus of about 1x10^6 human and non-human animal subjects [parameter 1] encompassed by the claims.
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.
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.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of delivering by intrathecal injection to a mouse subject a self-complementary AAV9 vector whose genome comprises the nucleotide sequence of SEQ ID NO:6, 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 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.
8. Claims 1-7 and 10-11 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Bevan et al (Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders, Molecular Therapy 19(11): 1971-1980, 2011) in view of Ikeda et al (Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer, J. Neurosurg. 91: 85-92, 1999; of record in IDS), Stankovic et al (U.S. 2018/0369414), Wu et al (WO 04/060270, *lengthy document, citation only), Le Meur et al (Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium, Gene Therapy 14:292-303, 2007), GenBank AF165426 (human NF2 gene, promoter region, July 26, 2016), and Chang et al (Multiple Transcription Initiation Sites, Alternative Splicing, and Differential Polyadenylation Contribute to the Complexity of Human Neurofibromatosis 2 Transcripts, Genomics 79(2): 63-76, 2002).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Bevan et al is considered relevant prior art for having taught a method of delivering a gene therapy vector to a subject in need (e.g. Title, “Gene Delivery….for Pediatric Disorders”), the method comprising the step of administering via intrathecal delivery an rAAV9 vector (e.g. pg 1975, col. 2, “we performed intrathecal… injections”) encoding the artisan’s transgene of interest, wherein the rAAV vector comprises a promoter operably linked to an intron, i.e. SV40 intron, operably linked to the transgene of interest (e.g. pg 1972, col. 1, Results, “AAV9-GFP with….an SV40 intron”).
Bevan et al taught that intrathecal injection of the rAAV9 vector resulted in extensive motor neuron transduction, as well as cerebellar Purkinje cells, nerve fibers within the medulla, and meningeal surfaces, indicating the majority of the rAAV9 virus was localized to the CNS (e.g. pg 1975, col. 2).
Bevan et al taught that intrathecal delivery is desirable because the ordinary artisan anticipates the potential requirement to avoid off-target expression of corrective transgenes outside the CNS. Development of an intrathecal delivery paradigm would reduce viral load that in turn could reduce the risk of an immune response as well as decrease viral production requirements particularly for older, presumably larger patients (e.g. pg 1978, col. 1).
Bevan et al do not teach wherein the rAAV9 gene therapy expression vector comprises a NF2 cDNA encoding a human Merlin protein with tumor suppressor activity.
However, prior to the effective filing date of the instantly claimed invention, Ikeda et al is considered relevant prior art for having taught an in vitro method of delivering a transgene encoding a human Merlin protein with tumor suppressor activity to human meningioma cells in need (e.g. Abstract, “primary human meningioma cells harvested from human tumors excised from patients….without NF2”), the method comprising the step of delivering to said human meningioma cells a gene therapy vector encoding a promoter operably linked to a human NF2 cDNA (e.g. pg 86, col’s 1-2, Methods; pg 88, col. 2).
Ikeda et al taught that over-expression of wildtype human NF2 had antiproliferative effects on the human meningioma cells (e.g. Figure 4, legend; pg 89, col. 2), and suggested that NF2 gene therapy may be useful in patients afflicted with NF2 (e.g. pg 90, col. 2, Discussion).
Similarly, Stankovic et al is considered relevant prior art for having disclosed a rAAV vector encoding NF2 (e.g. claim 6), wherein the rAAV vector comprises a promoter operably linked to an intron, i.e. beta-globin intron, operably linked to the transgene of interest (e.g. Example 3A, [0155], “intronic element”).
Wu et al is considered relevant prior art for having disclosed an expression vector comprising a NF2 cDNA (e.g. SEQ ID NO:1) encoding a Merlin protein, wherein the cDNA is 100% identical to nucleotides 530-2417 of instant SEQ ID NO:6 which encode a NF2 cDNA (search results available in SLIC).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice expression of a wildtype Merlin protein with tumor suppressor activity from a gene therapy expression vector comprising a human NF2 cDNA nucleotide sequence that is 100% identical to instant SEQ ID NO:6.
Neither Ikeda et al nor Wu et al taught/disclosed wherein the gene therapy expression vector comprising a human NF2 cDNA nucleotide sequence that is 100% identical to instant SEQ ID NO:6 is operably linked to a NF2 promoter.
However, prior to the effective filing date of the instantly claimed invention, Le Meur et al is considered relevant prior art for having taught a gene therapy method to treat a disease/disorder of the nervous system, the method comprising the step of administering to a subject in need a rAAV gene therapy expression vector comprising the artisan’s transgene cDNA of interest (RPE65) operably linked to a truncated version of said transgene’s promoter (RPE65) (e.g. Abstract, “rAAV vector carrying a human RPE65 cDNA driven by a human RPE65 promoter”; pg 300-301, Methods, AAV vector, “human RPE65 cDNA… fragment of the human PRE65 promoter”).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the use of a therapeutic transgene’s truncated human promoter to drive expression of a cDNA encoding said therapeutic transgene from a rAAV gene therapy vector in a method of gene therapy.
GenBank AF165426 is considered relevant prior art for having taught a polynucleotide comprising an NF2 promoter (e.g. SEQ ID NO:69880) that is 100% identical to nucleotides 1-400 of instant SEQ ID NO:6 (search results available in SLIC) operably linked to a NF2 protein-coding region.
Chang et al is considered relevant prior art for having taught an expression vector encoding a truncated human NF2 promoter operably linked to a 5’ untranslated region operably linked to a reporter gene (e.g. Figure 6). Chang et al taught the production of a series of 5’ truncated human NF2 promoters (e.g Figure 5), whereby the -400 to +1 promoter region was found to be the core promoter region (e.g. pg 70, col. 1, “core promoter region….is located within the D400 region of the human NF2 gene’s 5’ flanking DNA”), minimally sufficient to drive expression, and did not significantly affect the promoter activity.
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized and successfully reduced to practice the use of a human NF2 promoter comprising a nucleotide sequence that is 100% identical to the NF2 promoter nucleotide sequence of instant SEQ ID NO:6 to drive expression of the artisan’s gene of interest, whereby the human NF2 promoter was previously recognized to drive expression of a nucleic acid sequence encoding a human NF2 (syn. wildtype Merlin protein with tumor suppressor activity) protein.
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).”
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 and the design of gene therapy expression vectors. 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 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); 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 therapeutic transgene of interest, as taught by Bevan et al, with a second therapeutic transgene of interest, i.e. a NF2 cDNA encoding a human Merlin protein with tumor suppressor activity, as taught/disclosed by Ikeda et al and Stankovic et al, including a NF2 cDNA having 100% identity to nucleotides 530-2417 of instant SEQ ID NO:6, as disclosed by Wu et al, in a method of delivering a rAAV gene therapy expression vector to a subject in need via intrathecal delivery, 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 a first therapeutic transgene of interest with a second therapeutic transgene of interest, i.e. a NF2 cDNA encoding a human Merlin protein with tumor suppressor activity, including a NF2 cDNA having 100% identity to nucleotides 530-2417 of instant SEQ ID NO:6, in a method of delivering a rAAV gene therapy expression vector to a subject in need via intrathecal delivery because those of ordinary skill in the art have long-recognized that NF2 patients suffer from, e.g. CNS tumors such as meningiomas and schwannomas (e.g. Ikeda et al), whereby intrathecal injection of the rAAV9 vector resulted in extensive motor neuron transduction, as well as cerebellar Purkinje cells, nerve fibers within the medulla, and meningeal surfaces, indicating the majority of the rAAV9 virus was localized to the CNS, and that intrathecal delivery is desirable because the ordinary artisan anticipates the potential requirement to avoid off-target expression of corrective transgenes outside the CNS, as the intrathecal delivery paradigm would reduce viral load that in turn could reduce the risk of an immune response as well as decrease viral production requirements particularly for older, presumably larger patients (Bevan et al), and Ikeda et al taught that over-expression of wildtype human NF2 had antiproliferative effects on the human meningioma cells, and suggested that NF2 gene therapy may be useful in patients afflicted with NF2.
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).”
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first promoter operably linked to a NF2 cDNA, as taught by Ikeda et al, with a second promoter, i.e. a NF2 promoter, as taught by Chang et al, in a NF2 gene therapy expression vector, 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 promoter operably linked to a NF2 cDNA with a second promoter, i.e. a NF2 promoter, in a NF2 gene therapy expression vector, because those of ordinary skill in the art have long-recognized the scientific and technical concepts that:
i) the use of a therapeutic transgene’s truncated human promoter to drive expression of a cDNA encoding said therapeutic transgene from a rAAV gene therapy vector in a method of gene therapy (Le Meur et al);
ii) NF2 is naturally operably linked to a NF2 promoter; and
iii) Chang et al taught that the endogenous full-length human NF2 promoter is about 2400 nucleotides in length, but that a shorter, 400 nucleotide fragment proximal to the transcription start site (syn. -400) is the “core promoter region” that does not significantly affect promoter activity and is minimally sufficient to drive expression of the operably linked transgene in human cells, including teratocarinoma and neuroblastoma cells (e.g. pg 70, Figure 5). Chang et al taught that NF2 cDNAs may be as long as 2000 nucleotides (e.g. pg 63, col. 2), and thus the combination of a 2400 nucleotide promoter and a 2000 nucleotide cDNA would be pushing, if not exceeding, the structural limits of, e.g. a rAAV expression vector whose natural packaging size is only about 4700 nucleotides. However, a minimal core promoter of only about 400 nucleotides would still allow for the other structural and regulatory elements of an rAAV expression vector.
Nucleotides 1-400 of SEQ ID NO:6 are disclosed to encode a NF2 promoter.
Thus, the breadth of the claims reasonably encompasses as many as 248 nucleotides in the NF2 promoter that are modified, resulting in only about 62% identity to nucleotides 1-400.
Even if one were to limit the genus of NF2 promoter variants to be at least 90% identical to nucleotides 1-400 of SEQ ID NO:6, such allows for as many as 40 nucleotide insertions, deletions, and/or substitutions.
See discussion in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
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.
Instant specification fails to disclose an element of criticality for the NF2 promoter nucleotide sequence of 1-400 of instant SEQ ID NO:6, as opposed to the core minimal human NF2 promoter identified by Change et al.
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).”
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Nucleotides 413-512 (99 nucleotides) of SEQ ID NO:6 are disclosed to encode an SV40 intron.
Claim 1 recites a gene therapy vector comprising the polynucleotide of SEQ ID NO:6 (2483 nucleotides), or at least 90% identity thereto, which allows for as many as 248 nucleotide insertions, deletions, and/or substitutions distributed anywhere in SEQ ID NO:6.
See discussion in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Thus, the breadth of the independent claim is such that the SV40 intron of instant SEQ ID NO:6 need not even be present, while also allowing as many as 149 nucleotide insertions, deletions, and/or substitutions distributed elsewhere in SEQ ID NO:6, e.g. the NF2 promoter and/or the NF2 cDNA, for example.
Thus, as evidenced by the independent claim, the presence of the SV40 intron is not considered dispositive and/or controlling for patentability.
Similarly, nucleotides 413-512 of SEQ ID NO:6, and/or 90% identity thereto, are not considered dispositive and/or controlling for patentability.
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.
Instant specification fails to disclose an element of criticality for:
i) the heterologous SV40 intron nucleotide sequence of 413-512 of instant SEQ ID NO:6; as opposed to
ii) some other heterologous SV40 intron having at least 90% identity to nucleotides 413-512 of SEQ ID NO:6; let alone
iii) the heterologous SV40 intron of the prior art (Bevan et al); let alone
iv) some other heterologous intron, e.g. human beta-globin intronic element (Stankovic et al),
in a rAAV gene therapy expression vector.
Rather, the substantive issue is that those of ordinary skill in the prior art previously recognized and successfully reduced to practice the design and synthesis of rAAV gene therapy expression vectors comprising the artisan’s promoter of interest operably linked to a heterologous intron, including an SV40 intron, operably linked to a cDNA encoding the artisan’s transgene of interest.
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).”
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
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 Claim 10, Bevan et al taught wherein the rAAV is AAV9 (entire paper), being desirable because it is an art-recognized “powerful tool for delivering genes throughout the central nervous system”, including it’s art-recognized ability to cross the blood-brain-barrier (e.g. Abstract).
Stankovic et al disclosed wherein the rAAV is AAV9 (e.g. Figures 1, 4, and 6).
With respect to Claims 2-7, Ikeda et al taught that NF2 disorder is inherited as an autosomal dominant disorder, whereby patients commonly have at least one defective NF2 allele (e.g. pg 85, col. 1, Introduction), said NF2 patients suffering from, e.g. brain tumors, vestibular schwannomas, meningeomas, and ependymomas (e.g. pg 85, col. 1, Introduction).
Claims 3-7 do not further limit the independent claim. See the above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
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, the invention as a whole is prima facie obvious.
9. Claim(s) 10 and 12 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Bevan et al (2011; of record) in view of Ikeda et al (1999; of record in IDS), Stankovic et al (U.S. 2018/0369414; of record), Wu et al (WO 04/060270; of record), Le Meur et al (2007; of record), GenBank AF165426 (July 26, 2016; of record), and Chang et al (2002; of record), as applied to Claims 1-7 and 10-11 above, and in further view of Castle et al (Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion, Science Advances 4: eaau9859, 11 pages, doi: 10.1126/sciadv.aau9859; available online November 14, 2018).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Bevan et al, Ikeda et al, Wu et al, Le Meur et al, Chang et al, nor Stankovic et al teach/disclose placing the subject in the Trendelenburg position after intrathecal administration of the gene therapy vector.
However, prior to the effective filing date of the instantly claimed invention, Castle et al is considered relevant prior art for having taught a method of delivering an rAAV9 gene therapy vector to a subject via intrathecal delivery (e.g. Title), wherein the method further comprises the step of placing the subject in the Trendelenburg position after intrathecal administration of the gene therapy vector (e.g. pg 1, col.s 1-2, Introduction; pg 1, col. 2, Results, “Trendelenburg position”). Castle et al taught that because AAV9 distribution in the CSF is affected by gravity, placing the subject in the Trendelenburg position after intrathecal administration of the gene therapy vector significant enhances gene delivery to the brain (e.g. pg 1, col. 2; pg 4, col. 1; pg 5, col. 2, “Trendelenburg position enhances gene transfer to the brain…., the number of transduced brain cells is significantly increased by more than 15-fold”).
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); 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 the method of Bevan et al to further comprise the step of placing the subject in the Trendelenburg position after intrathecal administration of the gene therapy vector with a reasonable expectation of success because Castle et al taught that because AAV9 distribution in the CSF is affected by gravity, placing the subject in the Trendelenburg position after intrathecal administration of the gene therapy vector significant enhances gene delivery to the brain (e.g. pg 1, col. 2; pg 4, col. 1; pg 5, col. 2, “Trendelenburg position enhances gene transfer to the brain…., the number of transduced brain cells is significantly increased by more than 15-fold”).
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 Claim 10, Bevan et al taught wherein the rAAV is AAV9 (entire paper), being desirable because it is an art-recognized “powerful tool for delivering genes throughout the central nervous system”, including it’s art-recognized ability to cross the blood-brain-barrier (e.g. Abstract).
Stankovic et al disclosed wherein the rAAV is AAV9 (e.g. Figures 1, 4, and 6).
Castle et al taught wherein the rAAV is AAV9 (entire paper).
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, the invention as a whole is prima facie obvious.
Citation of Relevant Prior Art
10. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Meyer et al (WO 21/077115; filed October 19, 2020; priority to October 18, 2019) is considered relevant prior art for having disclosed a rAAV vector encoding a therapeutic transgene, wherein the rAAV vector comprises a promoter operably linked to an SV40 intron operably linked to the transgene of interest (e.g. Figure 1).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific and technical concepts of rAAV vector comprising a promoter-SV40 intron- transgene of interest encoding nucleic acid.
Trinklein et al (U.S. 2009/0018031) is considered relevant prior art for having disclosed an expression vector comprising an NF2 promoter (e.g. SEQ ID NO:2211) that is 100% identical to nucleotides 1-400 of instant SEQ ID NO:6 (search results available in SLIC).
Liu et al (WO 18/204764; *lengthy document, citation only) is considered relevant prior art for having disclosed an expression vector comprising an NF2 promoter (e.g. SEQ ID NO:69880) that is 100% identical to nucleotides 1-400 of instant SEQ ID NO:6 (search results available in SLIC).
Conclusion
11. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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