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 February 3, 2026.
Amendments
Applicant's response and amendments, filed February 3, 2026, are acknowledged. Applicant has cancelled Claims 1-26, 43-48, 51-57, and 61, and amended Claims 27 and 60.
Claims 27-42, 49-50, and 58-60 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative pharmaceutical to be administered to the subject is an isolated Vgamma4+ cell expressing a heterologous protein, as recited in Claims 27(a) and 42(b); and
ii) the alternative mutation to be identified/compared is a mutation in a polynucleotide sequence encoding BTNL3 and/or BTNL8, as recited in Claims 28, 42(a), and 58(a).
Claims 27-42, 49-50, and 58-60 are pending.
Claims 29, 31, and 35 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.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 27-28, 30, 32-34, 36-42, 49-50, and 58-60 are under consideration.
Priority
This application is a division of application 16/646,914 filed on March 12, 2020, now abandoned, which is a 371 of PCT/EP2018/075102 filed September 17, 2018. Applicant’s claim for the benefit of a prior-filed application provisional application 62/559,225 filed on September 15, 2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The Examiner also acknowledges co-pending application 18/448811, which is a continuation of application 16/646,914 filed on March 12, 2020, now abandoned, which is a 371 of PCT/EP2018/075102 filed September 17, 2018.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on January 9, 2024 that has been considered.
The information disclosure statement filed January 9, 2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citation 1 has been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claim 40 is objected to because of the following informalities:
The claim recites IBD; however, the claim does not first identify IBD by its complete name prior to using the acronym. The abbreviation should be spelled out in the first appearance of the claims and should be followed by the abbreviation in parentheses.
Appropriate correction is required. See, for example, Claim 30, single nucleotide polymorphism (SNP).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
2. Claims 49-50 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) “used to diagnose the patient as having cancer”.
With respect to Step 1, the claims are directed to a process, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, the claims are direct to “comparing a level of a polynucleotide sequence….with a reference level”, whereby the step of comparing is an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, the claims do not recite additional elements that integrate the judicial exception into a practical application. Rather, the step of comparing levels of an experimental sample to a reference sample is considered merely extra-solution activity within the medical diagnostic and or laboratory research field of use. Thus, the claim does not integrate the mental analysis step into a practical application. It is thus extra-solution activity, and does not integrate the judicial exception into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, the inventive concept is the detection of a polynucleotide sequence associated with a mutation in the BTNL3 and/or BTNL8 gene(s) that is present in the sample from which the artisan thus performs the mental step of comparing. Thus, the claim is not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
3. Claims 58-60 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) “used to diagnose the patient as having cancer”.
With respect to Step 1, the claim is directed to a process, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, the claim is direct to identifying (syn. diagnosing) a patient as being likely to develop inflammatory bowel disease (IBD), whereby the step of identifying or diagnosing is an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, the claim does not recite additional elements that integrate the judicial exception into a practical application. While Claim 58 recites a step of treating the subject with a pharmaceutical composition according to Claim 27, said Claim 27 recites a genus of structurally different formularies, each recited at a high level of generality. See further discussion below in 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Thus, the claim does not integrate the mental analysis step into a practical application. (Step 2A, prong two: NO).
The claim does not recite additional elements, e.g., to effect a particular treatment for the generically recited IBD patient.
With respect to Step 2B, the inventive concept is the identification of a BTNL3 and/or BTNL8 mutation, e.g. a deletion variant that produces a BTNL8*3 fusion protein, in a human patient, from which the artisan thus performs the mental step of diagnosing (syn. identifying). Thus, the claim is not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
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.
4. Claims 49-50 and 59 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.
As a first matter, Claims 49 and 59 recite the limitation “the mutation”. There is insufficient antecedent basis for this limitation in the claim because the (a) embodiment is directed to the detection of a sequence “associated with” a deletion variant, not the deletion variant itself. It is unclear if the limitation “mutation” refers to the deletion variant, or the other sequence “associated with”, but is not, the deletion variant. The limitation “mutation” is broader in scope and not identical to “deletion variant”.
As a second matter, the phrase “a reference level” is a relative phrase which renders the claim indefinite. The phrase “reference level” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
If there are multiple reference levels of BTNL3 and/or BTNL8 from which increased or decreased level(s) is/are to be determined, yet each yields a different result, then the claim may be indefinite because it is unclear which of the reference expression level value is/are to be referenced in order to determine infringement.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
5. Claims 49-50 and 59 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(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Claims 49 and 59 are directed to the detection of a sequence “associated with” a deletion variant, not the deletion variant itself.
Instant claims fail to recite, and the specification fails to disclose, the identity of a polynucleotide sequence that is “associated with” a deletion variant, but is not the deletion variant itself, whose level is to be compared in the sample.
Those of ordinary skill in the art immediately recognize that “associated with” does not have the same meaning as the actual deletion itself. Rather, it is an indirect object.
The phrase “associated with” may exist anywhere in the human genome and/or chromosome that also encodes BTNL3 and/or BTNL8.
The specification fails to disclose what sequence(s) that are not the actual deletion is/are “associated with” the deletion variant, as opposed to sequence(s) that are not the actual deletion is/are not “associated with” the deletion variant.
The specification fails to disclose what sequence(s) that are not the actual deletion is/are “associated with” the deletion variant and are to be compared to the reference level, thereby identifying a mutation and/or deletion variant, as opposed to sequence(s) that are not the actual deletion is/are not “associated with” the deletion variant and are to be compared to the reference level, thereby identifying a mutation and/or deletion variant.
At best, the specification discloses detection of the prior art recognized deletion that produces a BTNL8*3 fusion protein (pg 20, lines 14-16), not some structurally undisclosed polynucleotide hypothetically “associated with” said deletion.
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.
6. Claims 27-28, 30, 32-34, and 36-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase “relative to a reference expression level” in Claim 27 is a relative phrase which renders the claim indefinite. The phrase “relative to a reference expression level” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
If there are multiple reference expression levels of BTNL3 and/or BTNL8 from which decreased expression level(s) is/are to be determined, yet each yields a different result, then the claim may be indefinite because it is unclear which of the reference expression level value is/are to be referenced in order to determine infringement.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
7. Claims 27-28, 30, 32-34, and 36-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims are directed to methods of treating gut inflammation in a subject, the method comprising the step of administering to the subject a composition comprising:
i) an isolated Vgamma4+ (Vg4+) cell expressing a heterologous protein.
While independent Claim 27 does not recite ipsis verbis “an effective amount”, 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 pharmaceutical composition must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
It is apparent that the amount must be therapeutic. Even so, the various endpoints and extents that define effective treatment are more of a conditional or qualitative nature. As such, it is not evident what effect is necessarily achieved. Rather, the expected or desired effect that is to be achieved in the practice of the claimed invention to treat the patient is considered highly subjective and would tend to vary substantially.
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 subject(s) to be treated [parameter 1];
the structure(s) of pharmaceutical composition that is to be administered [parameter 2];
the structure and function of the heterologous protein expressed by the Vg4+ cell [parameter 3];
the dosage administered [parameter 4];
the administration route [parameter 5];
the disease/disorder/condition to be treated [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” (syn. a sub-therapeutic amount).
Parameter 1
The claims are broad for encompassing about 1,000,000 species of human and non-human animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, mice, and rats, 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 specification discloses wherein the subject is a human subject (e.g. pg 19, line 23).
Parameter 2
Claim 27(a) merely requires administration to the subject a single Vgamma4+ cell expressing a heterologous protein.
Parameter 3
The claimed methods are recited at a high level of generality for the genus of structurally and functionally unrecited and undisclosed heterologous protein(s) that is/are to be expressed by the Vg4+ cell.
Tiessen et al (Mathematical modeling and comparison of protein size distribution in different plant, animal, fungal and microbial species reveals a negative correlation between protein size and protein number, thus providing insight into the evolution of proteomes, BMC Research Notes 5: e85, doi.org/10.1186/1756-0500-5-85; 2012) is considered relevant prior art for having taught that the average eukaryotic protein is about 475 amino acids in length (e.g. Abstract).
20^475 is an infinite genus of structurally and functionally undisclosed proteins.
(www.calculator.net/exponent-calculator.html; last visited March 2, 2026).
The specification discloses the heterologous protein may be CD3, Vg4, Vdelta 1, or Vdelta 3 (e.g. pg 4, lines 25-26), or a marker protein, such as a fluorescent protein (e.g. pg 23, line 14).
Parameter 4
The claimed methods are recited at a high level of generality for the genus of structurally and functionally unrecited and undisclosed pharmaceutical composition comprising the single Vgamma4+ cell expressing a heterologous protein, and their corresponding dosages.
The specification discloses, for example, a cellular pharmaceutical comprising 10^6 to 10^10 cells (e.g. pg 3, line 7), for which just one of the cells need be a Vg4+ cell expressing a heterologous protein.
The structure and function identity of the other cell type(s) present in the cell pharmaceutical is/are unknown, be they fibroblasts, myocytes, endothelial cells, lymphocytes, stem cells, neuronal cells, bacterial cells, etc…
Parameter 5
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally (e.g. pg 24, lines 21-28).
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct gut inflammation diseases/disorders/conditions, including, but not limited to inflammatory bowel disease, ulcerative colitis, Crohn’s disease, colorectal cancer, colon cancer, rectal cancer, anal cancer, hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), small intestine cancer (e.g., adenocarcinoma, sarcoma, gastrointestinal carcinoid tumours, lymphoma, or gastrointestinal stromal tumours), and small bowel cancer. In some embodiments, the cancer is a gastrointestinal cancer, such as non-metastatic or metastatic colorectal cancer, pancreatic cancer, gastric cancer, or hepatocellular cancer (e.g. pgs 27-28, joining para).
Parameter 7
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 specification discloses that “treating” encompasses:
i) achieve a desired therapeutic effect (e.g. pg 24, line 10), which itself is an arbitrary and subjective determination;
ii) inhibit the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject (e.g. pg 24, lines 10-14); and
ii) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival (e.g. pg 28, lines 12-15).
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025)
Munn (Cancer and inflammation, WIREs Systems Biology and Medicin 9(2): e1370, abstract only, doi.org/10.1002/wsbm.1370; available online December 12, 2016) is considered relevant prior art for having taught that chronic inflammation in inflammatory gut diseases/disorders/conditions can induce cancer.
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)).
If there are multiple ways to measure “therapeutically effective dose”, to wit, cell pharmaceutical composition and their corresponding functional properties, structure(s)/function(s) of the expressed heterologous protein(s), cell pharmaceutical dosages, anatomical administration routes, disease to be treated, 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.
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.
8. Claims 27-28, 30, 32-34, and 36-38 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(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
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 subject(s) to be treated [parameter 1];
the structure(s) of pharmaceutical composition that is to be administered [parameter 2];
the structure and function of the heterologous protein expressed by the Vg4+ cell [parameter 3];
the dosage administered [parameter 4];
the administration route [parameter 5];
the disease/disorder/condition to be treated [parameter 6]; and
the phenotypic response to be achieved [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” (syn. a sub-therapeutic amount).
Claim 27(a) merely requires administration to the subject a single Vgamma4+ cell expressing a heterologous protein.
The art does not teach, and the specification fails to disclose, that administration of just one Vgamma4+ cell expressing a heterologous protein will necessarily and predictably achieve a real-world, clinically meaningful treatment of gut inflammation in the enormously vast genus of about 1x10^6 human and non-human animal subjects.
The specification is silent to administration of Vg4+ cells expressing a heterologous protein to a human patient suffering from gut inflammation.
Example 11 is merely prophetic. Disclosed at a high level of generality and no reduction to practice.
Parameter 8
Claims 36-38 recite wherein the method further comprises the step of administering to the subject a polynucleotide encoding an HNF4A protein.
The specification discloses the HNF4A protein refers to any functional HNF4A protein, from any primate source, including humans (e.g. pg 20, lines 21-22; SEQ ID NO:9, 392 amino acids) or mammalian (mouse) orthologue thereof (e.g. pg 20, line 27 (mouse orthologue, SEQ ID NO:12, 474 amino acids).
The specification discloses the HNF4A protein need only have at least 55%, 60%, 65%, 70%, 80%, 90%, 95%, or 99% identity to a reference SEQ ID NO (e.g. pg 22, lines 2-4).
20^176 (55% identity to SEQ ID NO:9) = about 9x10^228.
20^157 (60% identity to SEQ ID NO:9) = about 2x10^204.
20^137 (65% identity to SEQ ID NO:9) = about 2x10^178.
20^118 (70% identity to SEQ ID NO:9) = about 3x10^153.
20^78 (80% identity to SEQ ID NO:9) = about 3x10^101.
20^39 (90% identity to SEQ ID NO:9) = about 5x10^50.
20^20 (95% identity to SEQ ID NO:9) = about 1x10^26.
20^213 (55% identity to SEQ ID NO:12) = about 1x10^277.
20^190 (60% identity to SEQ ID NO:12) = about 1x10^247.
20^166 (65% identity to SEQ ID NO:12) = about 9x10^215.
20^142 (70% identity to SEQ ID NO:12) = about 5x10^184.
20^95 (80% identity to SEQ ID NO:12) = about 4x10^123.
20^47 (90% identity to SEQ ID NO:12) = about 1x10^61.
20^24 (95% identity to SEQ ID NO:12) = about 1x10^31.
Thus, the breadth of the claims reasonably encompass an enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins, and variants thereof.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins thereof that will necessarily and predictably have the functional properties of being transcription factor, thereby regulating the expression of its corresponding genus of target genes.
Parameter 9
The claimed methods are recited at a high level of generality for type of polynucleotides encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins, said polynucleotides including, but not limited to 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 10
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 11
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally (e.g. pg 24, lines 21-28).
The claims fail to recite, and the specification fails to disclose, a first cellular composition [parameter 2], including but not limited to comprising just one Vg4+ cell expressing an infinite genus of structurally and functionally undisclosed heterologous protein [parameter 3], and its corresponding dosage [parameter 4] administered via a first administration route, e.g. subcutaneously [parameter 5], to a first subject, e.g. a pig [parameter 1], that is necessarily and predictably able to prevent colon cancer [parameters 6-7], as opposed to a second cellular composition [parameter 2], including but not limited to comprising just one Vg4+ cell expressing an infinite genus of structurally and functionally undisclosed heterologous protein [parameter 3], and its corresponding dosage [parameter 4] administered via a second administration route, e.g. intrapericardially [parameter 5], to a second subject, e.g. a mouse [parameter 1], that is necessarily and predictably able to cause total remission of Crohn’s disease [parameters 6-7], for example.
The claims fail to recite, and the specification fails to disclose, a first cellular composition [parameter 2], including but not limited to comprising just one Vg4+ cell expressing an infinite genus of structurally and functionally undisclosed heterologous protein [parameter 3], and its corresponding dosage [parameter 4] administered via a first administration route, e.g. peritoneally [parameter 5], to a first subject, e.g. a dog [parameter 1], that is necessarily and predictably able to reduce colon cancer metastasis [parameters 6-7], as opposed to a second cellular composition [parameter 2], including but not limited to comprising just one Vg4+ cell expressing an infinite genus of structurally and functionally undisclosed heterologous protein [parameter 3], and its corresponding dosage [parameter 4] administered via a second administration route, e.g. intrathecally [parameter 5], to a second subject, e.g. a human [parameter 1], that is necessarily and predictably able to cause prolonged survival of ulcerative colitis [parameters 6-7], for example.
The claims fail to recite, and the specification fails to disclose, a first polynucleotide composition [parameter 9], e.g. bacterial artificial chromosome, encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8], and its corresponding dosage [parameter 10], administered via a first administration route, e.g. subcutaneously [parameter 11], to a first subject, e.g. a rabbit [parameter 1], that is necessarily and predictably able to prevent colon cancer [parameters 6-7], as opposed to a second polynucleotide composition [parameter 9], e.g. bacteriophage, encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8], and its corresponding dosage [parameter 10], administered via a second administration route, e.g. intramuscularly [parameter 11], to a second subject, e.g. a dog [parameter 1], that is necessarily and predictably able to cause total remission of Crohn’s disease [parameters 6-7], for example.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
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 pharmaceutical composition is to comprise at least one Vg4+ cell expressing a heterologous protein does not tell you anything at all about:
i) the enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions that are to be administered [parameter 2];
ii) an infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3] to be expressed by the Vg4+ cell;
iii) the enormously vast genus of cell pharmaceutical dosages to be administered [parameter 4]; and
iv) the enormous genus of anatomical administration routes [parameter 5] including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2] comprising at least one Vg4+ cell expressing the infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3], and the corresponding enormously vast genus of cell pharmaceutical dosages [parameter 4] are to be administered;
so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result for the enormously broad genus of diseases/disorders/conditions to be treated [parameter 6], including, but not limited to:
a) the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject; and/or
b) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival [parameter 7],
in the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1] encompassed by the claims, nor
v) the broadly claimed genus of polynucleotide compositions [parameter 9];
vi) the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8];
vii) the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8]; and
viii) the enormous genus of anatomical administration routes [parameter 11] including, but including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] and the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] are to be administered to the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [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) an enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions that are to be administered [parameter 2];
ii) an infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3] to be expressed by the Vg4+ cell;
iii) an enormously vast genus of cell pharmaceutical dosages to be administered [parameter 4]; and
iv) an enormous genus of anatomical administration routes [parameter 5] by which said enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2] comprising at least one Vg4+ cell expressing the infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3], and the corresponding enormously vast genus of cell pharmaceutical dosages [parameter 4] are to be administered; and
v) an enormously broad genus of diseases/disorders/conditions to be treated [parameter 6];
vi) an enormously vast genus of phenotypic or therapeutic results, including, but not limited to:
a) the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject; and/or
b) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival [parameter 7],
in the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1], nor
v) the broadly claimed genus of polynucleotide compositions [parameter 9];
vi) the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8];
vii) the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8]; and
viii) the enormous genus of anatomical administration routes [parameter 11] including, but including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] and the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] are to be administered to the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1] encompassed by the claims.
“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.
Example 11 is merely prophetic. Disclosed at a high level of generality and no reduction to practice.
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.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
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.
9. Claims 27-28, 30, 32-34, and 36-38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while enabling for a method of increasing the number of Vg4+ cells in a mouse subject suffering from gut inflammation, the method comprising the step of intravenously administering a pharmaceutical composition comprising at least 1x10^6 Vg4+ cells expressing a marker protein,
does not reasonably provide enablement for
i) the enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions that are to be administered [parameter 2];
ii) an infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3] to be expressed by the Vg4+ cell;
iii) the enormously vast genus of cell pharmaceutical dosages to be administered [parameter 4]; and
iv) the enormous genus of anatomical administration routes [parameter 5] by which said enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2] comprising at least one Vg4+ cell expressing the infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3], and the corresponding enormously vast genus of cell pharmaceutical dosages [parameter 4] are to be administered;
so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result for the enormously broad genus of diseases/disorders/conditions to be treated [parameter 6], including, but not limited to:
a) the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject; and/or
b) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival [parameter 7],
in the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1], nor
v) the broadly claimed genus of polynucleotide compositions [parameter 9];
vi) the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8];
vii) the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8]; and
viii) the enormous genus of anatomical administration routes [parameter 11] including, but including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] and the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] are to be administered to the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1] encompassed by the claims.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein 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 art does not teach, and the specification fails to disclose, that administration of just one Vgamma4+ cell expressing a heterologous protein will necessarily and predictably achieve a real-world, clinically meaningful treatment of gut inflammation in the enormously vast genus of about 1x10^6 human and non-human animal subjects.
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 pharmaceutical composition is to comprise at least one Vg4+ cell expressing a heterologous protein does not tell you anything at all about:
i) the enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions that are to be administered [parameter 2];
ii) an infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3] to be expressed by the Vg4+ cell;
iii) the enormously vast genus of cell pharmaceutical dosages to be administered [parameter 4]; and
iv) the enormous genus of anatomical administration routes [parameter 5] including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2] comprising at least one Vg4+ cell expressing the infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3], and the corresponding enormously vast genus of cell pharmaceutical dosages [parameter 4] are to be administered;
so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result for the enormously broad genus of diseases/disorders/conditions to be treated [parameter 6], including, but not limited to:
a) the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject; and/or
b) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival [parameter 7],
in the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1] encompassed by the claims, nor
v) the broadly claimed genus of polynucleotide compositions [parameter 9];
vi) the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8];
vii) the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8]; and
viii) the enormous genus of anatomical administration routes [parameter 11] including, but including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] and the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] are to be administered to the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [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) an enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions that are to be administered [parameter 2];
ii) an infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3] to be expressed by the Vg4+ cell;
iii) an enormously vast genus of cell pharmaceutical dosages to be administered [parameter 4]; and
iv) an enormous genus of anatomical administration routes [parameter 5] by which said enormously vast genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2] comprising at least one Vg4+ cell expressing the infinite genus of structurally and functionally undisclosed heterologous proteins [parameter 3], and the corresponding enormously vast genus of cell pharmaceutical dosages [parameter 4] are to be administered; and
v) an enormously broad genus of diseases/disorders/conditions to be treated [parameter 6];
vi) an enormously vast genus of phenotypic or therapeutic results, including, but not limited to:
a) the progression of the gut inflammation, delay progression of gut inflammation, reduce the rate of progress, halt the rate of progress, ameliorate the condition, cure the condition, cause partial remission, cause total remission, prevent the condition, delay, abate, or arrest at least one symptom of the condition, prolong survival of the subject; and/or
b) cause cancer remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor number, increase cancer cell death, increase time to tumor recurrence, or improve survival [parameter 7],
in the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1], nor
v) the broadly claimed genus of polynucleotide compositions [parameter 9];
vi) the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8];
vii) the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8]; and
viii) the enormous genus of anatomical administration routes [parameter 11] including, but including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, or intravitreally by which said broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] and the enormous genus of unrecited and undisclosed corresponding dosages [parameter 10], of the broadly claimed genus of polynucleotide compositions [parameter 9] encoding the enormously vast genus of about 10^277, ^247, ^228, ^215, ^204, ^184, ^178, ^153, ^123, ^101, ^61, ^50, ^31, and/or ^26 structurally and functionally undisclosed HNF4A proteins [parameter 8] are to be administered to the enormously vast genus of about 1x10^6 human or non-human animal subject(s) to be treated [parameter 1] encompassed by the claims.
“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.
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.
Maeda et al (Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs, Clinical and Translational Medicine 7: e11, 20 pages, doi.org/10.1186/s40169-018-0185-6; available online March 1, 2018) is considered relevant prior art for having taught that recent immunotherapy for solid tumors (e.g. ovarian cancer) produced outcome failure-rates of 90% (Abstract). Despite the initial enthusiasm for site-specific cancer, the outcomes are bleak and disappointing. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. Other recently published articles on basic research and clinical studies of cancer and pathogen-specific vaccines have raised serious concerns about the worthiness, hidden agenda and high costs of these reductionist approaches to such projects that are toxic and repeatedly failed the public (pg 2, col. 1).
While the isolated molecular entities are parts of the highly heterogeneous and chaotic landscape in cancer biology, they should not be considered as ‘target’ for therapy as they have little/no value on their own for translational purposes although theymay work in mouse models for the selected conditions and duration of therapy which do not apply to human (e.g. pg 2, col’s 1-2, joining para).
The decision makers of such expensive, out-of-focus and fuzzy undertakings seldom consider the life-threatening consequences of wrong and reductionist approaches to drug development for patients and the tremendous economic burden to the society. The irresponsible decision makers of such undertakings, either abandon data on failed outcomes or downplay and ignore the serious consequences of drugs (pg 2, col. 2).
Recent attempts on extensive trials of cancer vaccines, using viral structures or substructures against several cancers such as cervices, prostate, lung, pancreatic and skin also failed to produce the overall protective clinical outcomes. While the prophylactic vaccinations could be the most effective and rational medical preventive strategies, their systemic immunity and effectiveness against cancer is debatable. The elaborate epitopic targets of cancer seem to have limited prospects and therapeutic cancer vaccination is an area of questionable efficacy for immunotherapy and safety (pg 3, col. 2).
As recently reported, a closer look at cancer science reveals that highly powered structure (hierarchy) in cancer/medical establishment (system) versus antisystem and chaotic approaches to cancer research and therapy (‘medical/scientific ponzi schemes’) are potent recipes for failed therapeutics that kills patients but generates huge corporate profit (pg 4, col. 1). Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients. In these studies, little considerations are given to the cellular immune composition of site-specific tissues, the immune-non-immune local or systemic compensatory response mechanisms, the bioenergetics and oxido redox profiles of tissues toward checkpoint inhibition, as well as, the host immune and non-immune interactions with recruited cells and the adverse responses that are observed following therapy (pg 4, col. 1).
Targeting genetic mutations in site-specific solid cancers that produced repeatedly failed outcomes while generated huge corporate profits. Molecular target drugs created great business motives for drug industry to focus on them in the last six decades. After revealing extremely high incidence of mutations in solid cancer, very little scientific rationale has been presented for developing such costly molecular target drugs that are based on identification of too many evolving genetic mutations in the chaotic cancer environments (pg 5, col. 2). Ovarian cancers may comprise as many as 30-60 different mutations (Table 1).
Evaluation of some drug encapsulated liposomes and micellar nanoparticles reveal another example of failed attempts in cancer chemotherapy. Nanotechnology-based nanomedicine has been the focus of great attention in the past couple of decades. Initially, liposome particles presented the poorest outcomes in the pharmacokinetics because of little considerations of the rapid clearance and removal of nanoparticles by phagocytic cells (pg 9, col. 2).
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed (pg 10, col. 2).
Prohibitive costs of cancer therapy with repeatedly failed outcomes. Economic impact on medical insurance, and unbearable burden to the society. A serious problem in current cancer chemotherapy involves the cost of care for cancer patients, particularly the astronomical costs of recently claimed molecular ‘targeted’ drug, ‘personalized’ or ‘precision’ medicine with outcome failure rates of 85–95%. While majority of such drugs produced no reasonable benefit to meaningfully extend survival of cancer patients, particularly those with solid tumors, they are tremendously costly for the patients, their families and the public (pg 13).
Concerned voices of independent and competent professionals, oncologists and scientists that are raised for seeking the truth in cancer science, on behalf of the cancer-stricken public for changing the directions in cancer research or therapy or safety and unethical motives behind development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers. We also suggested that the USA policy makers and medical/cancer establishment to return to ‘common sense’ that our forefathers used to serve the public (pg 14, col. 1).
Saxena et al (Therapeutic Cancer Vaccines, Nature Reviews 21: 360-378, June 2021) is considered relevant post-filing art for having taught that the goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal, resulting in the failure of cancer vaccines (Abstract). The aim of therapeutic cancer vaccines is to stimulate the patient’s adaptive immune system against specific tumour antigens to regain control over tumour growth, induce regression of established tumours and eradicate minimal residual disease. The basic principles needed for successful therapeutic vaccination against tumours include delivery of large amounts of a high-quality antigen to DCs, optimal DC activation, induction of strong and sustained CD4+ T helper cell and cytotoxic T lymphocyte (CTL) responses, infiltration of the TME and durability and maintenance of response (pg 360, col. 2).
Despite the FDA approval of a DC-focused cell-based vaccine, sipuleucel-T, more than 10 years ago, no other therapeutic cancer vaccine has been approved. It is now appreciated that tumour cell intrinsic resistance and local or systemic immunosuppressive (extrinsic) mechanisms substantially compromise the efficacy of cancer vaccines (pg 361, col. 1). This led to a general disappointment in cancer vaccines after it was found that treatment with sipuleucel-T conferred only a small survival advantage in patients with prostate cancer. Moreover, a series of large phase III cancer vaccine studies in advanced disease reported negative outcomes. The complex set of host, tumour and environmental factors was not appreciated to have such a direct impact on tumour-specific immunity, and the design of cancer vaccines did not take into account all the mechanisms governing immune ignorance, exclusion, suppression and escape.
Consequently, these vaccines failed to generate the numbers of T cells or the durability of the T cell response required to elicit long-lasting immunity, making it evident that new strategies are required to overhaul the field’s approach to vaccine therapy. (pg 362, col. 1).
An obvious reason for the failure of cancer vaccines appears to be the choice of less immunogenic vaccine platforms or antigens, on the basis of the low percentage (11–50%) of patients showing a response to vaccination or the induction of non-effective allo-HLA-specific immune responses when allogeneic cell vaccines were used (pg 362, col. 2).
Additional issues regarding neoantigen vaccines include screening antigens for maximal clinical efficacy before vaccination, the number of neoepitopes to include in each vaccine and at what dosage, minimizing the lengthy vaccine production pipeline (currently around 3 months), the delivery platform, combination with ICI or other modalities and overcoming secondary mechanisms of resistance (pg 363, col. 2).
A big challenge in the field of therapeutic cancer vaccinology is ensuring the delivery of vaccine components to the appropriate compartment, be it the tumour-proximal secondary lymphoid organ or the TME. The anatomic location of the tumour, the baseline TME immune landscape, the mechanism of action of the vaccine and the biochemical properties of the vaccine components all need to be cumulatively considered before the best-suited delivery platform can be determined (pg 365, col. 1). Key determinants of antigen vaccine success appear to be (1) the type of antigens (MHC-I or MHC-II restricted), (2) the antigen dosing, (3) the adjuvant used and (4) the administration route (pg 365, col. 2).
Instant claims and specification fail to make up for the deficiencies of the global scientific community.
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).
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.
Example 11 is merely prophetic. Disclosed at a high level of generality and no reduction to practice.
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 claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claim(s) 49-50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aigner et al (A common 56-kilobase deletion in a primate-specific segmental duplication creates a novel butyrophilin-like protein, BMC Genetics 14: e61, 12 pages, biomedcentral.com/1471-2156/14/61; 2013; of record in specification).
With respect to Claims 49-50, Aigner et al is considered relevant prior art for having taught the detection, and comparisons relative to non-mutant, wildtype allele, of a deletion variant removing parts of the human BTNL3 and BTNL8 genes, thereby resulting in a BTNL8*3 fusion protein (e.g. Title, Abstract; Figure 1a; Figure 3a, 3c) present in lymphoblastoid cell lines (LCLs).
Aigner et al suggested determining the presence of disease-associated copy number variations in intestinal and digestive tract cells, including the BTNL3-BTNL8 mutation found in LCLs, because the LCLs are not the main cell type for BTNL3 and BTNL8 expression and it would be interesting to check for the consequences of the copy number variations in diseases associated with polymorphisms in BTNL genes in the intestine (e.g. pg 9, col. 1).
Thus, Aigner et al anticipate the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
11. Claim(s) 39-42 is/are rejected under AIA 35 U.S.C. 103 as being unpatentable over He et al (Naturally Activated Vgamma4 gamma/delta T cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin, J. Immunol. 185: 126-133, June 4, 2010; of record in IDS) in view of Roark et al (A canonical Vgamma4Vdelta4+ g/d T cell population with distinct stimulation requirements which promotes the Th17 response, Immunol. Res. 55: 217-230, available online September 9, 2012), and Murphy et al (Use of bioluminescence imaging to track neutrophil migration and its inhibition in experimental colitis cells, Clin. & Exp. Immunol. 162: 188-196, 2010).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 39, He et al is considered relevant prior art for having taught a method of administering a population of Vgamma4+ cells to a mammalian subject, to wit, a mouse subject (e.g. pg 127, col. 2, Results).
He et al taught that the Vgamma4+ cells had been screened for expression of Vgamma4 (e.g. pg 127, col. 1, Methods; pg 127, col. 2, “sorted… Vgamma4 gamma/delta T cells”).
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997). MPEP §2111.02
Instant subject and method step(s) is/are recited at a high level of generality, which He et al fulfill. Absent evidence to the contrary, it is considered natural law of cell biology, anatomy, and physiology that at least some of the thus-administered Vgamma4 gamma/delta T cells will migrate to the gut of the (mouse) subject, as Vgamma4+ T cells are recognized in the art to be highly motile and are naturally present in the intestinal epithelium, acting as sentinels that help prevent microbial infection (Roark et al, 2012; e.g. pg 217, col. 2; pg 225, col. 1).
While He et al taught the step of genetically modifying the Vgamma4 gamma/delta T cells to express a heterologous protein (e.g. pg 130, col. 2, “transduced with…..”), He et al do not teach the step of administering the genetically modified Vgamma4 gamma/delta T cells expressing the heterologous protein to the subject.
However, prior to the effective filing date of the instantly claimed invention, Murphy et al is considered relevant prior art for having taught a method of increasing the number of neutrophils expressing a heterologous protein in the gut of a mouse animal model of experimental colitis and inflammatory bowel disease (e.g. Title, Abstract), the method comprising the step of intravenously administering to said mouse subject a population of donor neutrophils expressing the heterologous protein luciferase (e.g. pg 190, col.s 1-2, joining para, Methods, Bioluminescence neutrophil tracking model).
Murphy et al taught that the neutrophil migration into the intestine is a major characteristic of inflammatory bowel disease, Crohn’s disease, and ulcerative colitis (e.g. pg 188, col. 1, Introduction).
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, immunology, and genetically modifying immune cells such as T lymphocytes. 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 modify the Vg4+ gamma/delta T cells of He et al to express a heterologous protein in a method of administering Vg4+ gamma/delta T cells to a subject with motivation and a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) Vg4+ gamma/delta T cells may be genetically modified to express a heterologous protein (He et al); and
ii) methods of increasing the number of the artisan’s immune cells of interest in the gut of a mouse animal model of experimental colitis and inflammatory bowel disease comprises the step of administering to said mouse subject a population of donor immune cells expressing the artisan’s heterologous protein of interest, e.g. a marker protein, thereby allowing the ordinary artisan to visualize or image the anatomical location(s) of the adoptively transferred cells in the body of the host subject, as successfully demonstrated by Murphy et al.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 40-41, Murphy et al taught that the neutrophil migration into the intestine is a major characteristic of inflammatory bowel disease, Crohn’s disease, and ulcerative colitis (e.g. pg 188, col. 1, Introduction).
With respect to Claim 42(b), He et al taught that the Vgamma4+ cells had been screened for expression of Vgamma4 (e.g. pg 127, col. 1, Methods; pg 127, col. 2, “sorted… Vgamma4 gamma/delta T cells”).
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.
12. Claim(s) 39-42 is/are rejected under AIA 35 U.S.C. 103 as being unpatentable over He et al (June 4, 2010; of record in IDS) in view of Roark et al (available online September 9, 2012; of record), and Murphy et al (2010; of record), as applied to Claims 39-42 above, and in further view of Lebrero-Fernandez et al (Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer, Immunity, Inflammation and Disease 4(2): 191-200, available online April 1, 2016; of record in IDS) and Aigner et al (2013; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither He et al, Roark et al, nor Murphy et al teach wherein the subject has a mutation in a polynucleotide sequence encoding BTNL3 and/or BTNL8.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 42(a), Lebrero-Fernandez et al is considered relevant prior art for having taught that expression of BTNL3 and BTNL8 are significantly decreased in human intestinal inflammatory conditions such as colon cancer and ulcerative colitis (e.g. Abstract; Figure 2).
Aigner et al is considered relevant prior art for having taught the detection of a deletion variant removing parts of the human BTNL3 and BTNL8 genes (e.g. Title, Abstract) present in lymphoblastoid cell lines (LCLs).
Aigner et al taught that BTNL3 and BTNL8 are predominantly expressed in the intestine and digestive tract, and suggested using such cells in determine disease-associated copy number variations, as was done with the lymphoblastoid cell lines (LCLs) because the LCLs are not the main cell type for BTNL3 and BTNL8 expression, and it would be interesting to check for the consequences of the copy number variations in diseases associated with polymorphisms in BTNL genes in the intestine (e.g. pg 9, col. 1).
The art recognizes that BNTL3 and BTNL8 are human genes, not expressed in mice.
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 mouse subject having an inflammatory bowel disease or ulcerative colitis with a human subject having an inflammatory bowel disease or ulcerative colitis in a method of increasing the number of Vg4+ gamma/delta T cells in the gut of said human subject, wherein the human has a mutation in a polynucleotide sequence encoding BTNL3 and/or BTNL8 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).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” 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 mouse subject having an inflammatory bowel disease or ulcerative colitis with a human subject having an inflammatory bowel disease or ulcerative colitis in a method of increasing the number of Vg4+ gamma/delta T cells in the gut of said human subject, wherein the human has a mutation in a polynucleotide sequence encoding BTNL3 and/or BTNL8 because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) expression of BTNL3 and BTNL8 are significantly decreased in human intestinal inflammatory conditions such as colon cancer and ulcerative colitis (Lebrero-Fernandez et al);
ii) BTNL3 and BTNL8 are predominantly expressed in the digestive tract (Aigner et al); and
iii) Aigner et al suggested determining the presence of disease-associated copy number variations in intestinal and digestive tract cells, including the BTNL3-BTNL8 mutation found in LCLs, because the LCLs are not the main cell type for BTNL3 and BTNL8 expression and it would be interesting to check for the consequences of the copy number variations in diseases associated with polymorphisms in BTNL genes in the intestine.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 40-41, Murphy et al taught that the neutrophil migration into the intestine is a major characteristic of inflammatory bowel disease, Crohn’s disease, and ulcerative colitis (e.g. pg 188, col. 1, Introduction).
Lebrero-Fernandez et al taught that expression of BTNL3 and BTNL8 are significantly decreased in human intestinal inflammatory conditions such as colon cancer and ulcerative colitis (e.g. Abstract; Figure 2).
Aigner et al taught that BTNL3 and BTNL8 are predominantly expressed in the digestive tract and intestine (pg 9, col. 1).
With respect to Claim 42(b), He et al taught that the Vgamma4+ cells had been screened for expression of Vgamma4 (e.g. pg 127, col. 1, Methods; pg 127, col. 2, “sorted… Vgamma4 gamma/delta T cells”).
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.
13. Claim(s) 27-28, 30, and 32-34 is/are rejected under AIA 35 U.S.C. 103 as being unpatentable over He et al (June 4, 2010; of record in IDS) in view of Roark et al (available online September 9, 2012; of record), Murphy et al (2010; of record), Lebrero-Fernandez et al (available online April 1, 2016; of record in IDS), and Aigner et al (2013; of record), as applied to Claims 39-42 above, and in further view of Hombach et al (Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity, Gene Therapy 16: 1088-1096, 2009), Wilkins et al (CAR T-Cell Therapy: Progress and Prospects, Human Gene Therapy Methods (Part B) 28(2): 61-66, doi.org/10.1089/hgtb.2016.153; available online April 1, 2017), Hao et al (Regulatory Role of Vgamma1 gamma/delta T cells in Tumor Immunity through IL-4 Production, J. Immunol. 187: 4979-4986, 2011), and Andreu-Ballester et al (Deficit of Gammadelta T Lymphocytes in the Peripheral Blood of Patients with Crohn’s Disease, Dig. Dis. Sci. 56: 2613-2622, 2011).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Claim interpretation:
While it is clear that the subject is to have decreased expression of BTNL3 and/or BTNL8 relative to an unidentified reference level (see 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection(s) above),
the breadth of the claimed subjects encompasses an enormously vast genus of about 1x10^6 human and non-human animal subjects (see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) above).
Those of ordinary skill in the art recognized that the mouse genome, for example, does not naturally encode BTNL3 and/or BTNL8.
Thus, per natural law of biology, it is axiomatic that mouse gut inflammatory models necessarily ‘have decreased expression levels of BTNL3 and/or BTNL8’, including decreased expression relative to, e.g. human BTNL3 and/or BTNL8 reference levels.
As discussed above, He et al, Murphy et al, Lebrero-Fernandez et al, and Aigner et al render obvious a method of increasing the number of Vg4+ gamma/delta T cells in a subject, including subjects suffering from inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, including human patients comprising a mutation in a polynucleotide sequence encoding BTNL3 and/or BTNL8.
Furthermore, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 27, Hombach et al is considered relevant prior art for having taught a method of adoptive immunotherapy for the treatment of an inflammatory bowel disease, e.g. colon cancer (e.g. pgs 1089-1090, joining para) or chronic colitis (e.g. pg 1092, col. 1), the method comprising the step of administering to the mouse subject human T cells genetically modified to express a chimeric antigen receptor that recognizes an antigen expressed on said colon cancer or chronic colitis intestinal epithelial cells.
Wilkins et al is considered relevant prior art for having taught that a number of studies have considered the use of chimeric antigen receptors for the treatment of inflammatory intestinal diseases and infections, e.g. irritable bowel syndrome (e.g. pgs 64-65, joining para).
Hao et al is considered relevant prior art for having taught that Vg4+ gamma/delta T cells play a protective role in tumor immunity (e.g. Abstract; pg 4981, Results, section headings, “Vg4 gamma/delta T cell-mediated antitumor immunity in vivo”, “Vg4 gamma/delta T cell-mediated tumor suppression in vitro”) in, at least, mouse subjects.
Andreau-Ballester et al is considered relevant prior art for having taught that gamma/delta T cells are an important component of innate immunity, and that patients suffering from Crohn’s disease demonstrate significantly reduced levels of gamma/delta T cells, including Vg4+ g/d T cells (e.g. pg 2615, col. 1, “recognizes all g/d T cell populations, regardless of the variable regions”), as compared to healthy patients (e.g. Abstract; Figure 1).
Andreau-Ballester et al taught that the art recognized that a decrease of gamma/delta T cells results in a deterioration of colitis histological lesions and an increased mortality in the mouse model system (e.g. pg 2614, col. 1).
Andreau-Ballester et al taught that one of the hypotheses to explain the etiology of Crohn’s disease is the immune-deficiency theory, in that defects of innate immunity is a primary factor for CD, and therefore, therapy should be aimed at bolstering innate immunity, not suppressing it (e.g. pg 2614, col. 2), whereby infusion of gamma/delta T cells in the mouse model system improves colitis histological lesions and an increases survival (e.g. pg 2614, col. 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re 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 treat gut inflammation in a mouse subject with a pharmaceutical composition comprising Vg4+ gamma/delta T cells expressing a heterologous protein, e.g. a marker protein, with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) adoptive immunotherapy of genetically modified lymphocytes expressing a heterologous protein in a method of adoptive immunotherapy for the treatment of an inflammatory bowel disease, e.g. colon cancer or chronic colitis, was previously known in the art (e.g. Hombach et al, Wilkins et al);
ii) Vg4+ gamma/delta T cells play a protective role in antitumor immunity and T cell-mediated tumor suppression in, at least, mouse subjects (Hao et al), whereby infusion of gamma/delta T cells in the mouse model system improves colitis histological lesions and an increases survival (Andreau-Ballester et al);
iii) BTNL3 and BTNL8 are predominantly expressed in the digestive tract of, at least, humans (Aigner et al); and
iv) expression of BTNL3 and BTNL8 are significantly decreased in human intestinal inflammatory conditions such as colon cancer and ulcerative colitis (Lebrero-Fernandez et al), and thus the mouse model system(s) of gut inflammation, ulcerative colitis, and/or colonic cancer may recapitulate one or more conditions of human intestinal inflammatory conditions such as colon cancer and ulcerative colitis.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 40-41, Murphy et al taught that the neutrophil migration into the intestine is a major characteristic of inflammatory bowel disease, Crohn’s disease, and ulcerative colitis (e.g. pg 188, col. 1, Introduction).
Lebrero-Fernandez et al taught that expression of BTNL3 and BTNL8 are significantly decreased in human intestinal inflammatory conditions such as colon cancer and ulcerative colitis (e.g. Abstract; Figure 2).
Aigner et al taught that BTNL3 and BTNL8 are predominantly expressed in the digestive tract and intestine (pg 9, col. 1).
With respect to Claim 42(b), He et al taught that the Vgamma4+ cells had been screened for expression of Vgamma4 (e.g. pg 127, col. 1, Methods; pg 127, col. 2, “sorted… Vgamma4 gamma/delta T cells”).
With respect to Claims 28, 30, and 32-34, Aigner et al taught wherein the mutation is a heterozygous deletion variant, resulting in a BTNL8*3 fusion protein (e.g. Abstract).
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
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hahn et al (Vgamma4+ gamma/delta T Cells Regulate Airway Hyperreactivity to Methacholine in Ovalbumin-Sensitized and Challenged Mice, J. Immunol. 171: 3170-3178, 2003) is considered relevant prior art for having taught a method of intravenous adoptive transfer of a population of about 2x10^4 lymphocytes comprising Vg4+ T cells to a mouse subject (e.g. pg 3171, col. 2, Methods, Adoptive transfer).
Conclusion
15. 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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