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 .
This Office Action is in reply to Applicants’ correspondence of 12/05/2025.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
New Claim Rejection – Necessitated by Amendments
Improper Incorporation by Reference of Essential Subject Matter
Claim Objection
Claim Rejection - 35 USC § 112 1st ¶ - Written Description
Claims 74 and 75 are objected to and rejected over recitation of the phrase “according to GRCh38/hg38 assembly coordinates”, as recited in each claims. The recitation (a reference to a Genome Reference Consortium Human Build and a UCSC Human Genome sequence version) is an attempt to improperly incorporate essential subject matter by reference. 37 CFR 1.57(d) provides:
“Essential material” may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference.
In the instant case, reference to a nucleotide sequence identified by nomenclature that is external to the USPTO and not fully defined in the application as originally filed is not appropriate for recitation of a claim limitation. Because the recitation is critical and essential to the practice of the claimed methods, the claims are thus also rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejection of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 2-3 of the Office Action of 09/11/2025, is withdrawn in light of the amendments to the claims.
New Claim Rejection – Necessitated by Amendments
Claim Rejections - 35 USC § 112 - Indefiniteness
Claims 18-22, 24, 31-34 and 75 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.
Claims 18-22, 24, 31-34 and 75 are unclear over the stated purpose of the claims a “treating a subject with a therapeutic agent that treats or prevents a metabolic disorder and a Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) inhibitor”, as recited in the preamble of claim 18, in light of the methods steps encompassed by the claims. Claim 18 includes “administering or continuing to administer the therapeutic agent that treats or prevents the metabolic disorder in an amount that is the same as a standard dosage amount to a subject that is homozygous for the MAP3K15 missense variant nucleic acid molecule” (recited in the third “administering” clause of claim18), which does not include any requirement for any MAP3K15 inhibitor. Thus it is unclear how the purpose of the claims, as set forth in the preamble of claim 18, is in fact accomplished when the methods includes a subject that is “homozygous for the MAP3K15 missense variant nucleic acid molecule”.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims under 35 U.S.C. 101, as set forth on pages 3-6 of the Office Action of 09/11/2025, is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 112 – Written Description
Maintained-in-Part, Modified as Necessitated by Claim Amendments
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.
Claims 1, 6, 13-22, 24, and 74-75 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties, ‘‘[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
‘‘[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A ‘‘representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The "structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875.
The requirements for an adequate written description of claimed subject matter is relevant to several aspects of the instantly claimed methods:
As a first aspects, claims 13-17 are drawn to methods that require detecting a MAP3K15 missense variant that is a predicted loss-of-function mutation.
Relevant to the breadth of genetic structures encompassed by the claims, the specification (p. 6-7) teaches:
“In any of the embodiments described herein, the MAP3K15 missense variant nucleic acid molecules encoding MAP3K15 predicted loss-of-function polypeptides can be any nucleic acid molecule (such as, for example, genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) encoding a MAP3K15 variant polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function. In some embodiments, the MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide is associated with a reduced in vitro response to MAP3K15 ligands compared with reference MAP3K15. In some embodiments, the MAP3K15 missense variant nucleic acid molecule encoding the MAP3K15 predicted loss-of-function polypeptide is a MAP3K15 variant that results or is predicted to result in a premature truncation of a MAP3K15 polypeptide compared to the human reference genome sequence. In some embodiments, the MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide is a variant that is predicted to be damaging by in vitro prediction algorithms such as Polyphen, SIFT, or similar algorithms. In some embodiments, the MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide is a variant that causes or is predicted to cause a nonsynonymous amino-acid substitution in MAP3K15 and whose allele frequency is less than 1/100 alleles in the population from which the subject is selected. In some embodiments, the MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide is any rare missense variant (allele frequency< 0.1%; or 1 in 1,000 alleles), or any splice-site, stop-gain, start-loss, stoploss, frameshift, or in-frame indel, or other frameshift MAP3K15 variant.”
The specification further provides a table of “MAP3K15 variants that can be used in the aggregate burden analysis”, as set forth on pages 31-102.
While the structures of the mutation encompassed by the claims are generically broad, here it is noted that even with regard to the specifically disclosed mutations it is not clear that the mutations have the required functionality of being “loss-of-function” mutations.
Even when a disclosed variant may encode a nonsynonymous mutation, it is not clear that such a mutation will be a loss-of-function. For example, the substitution of amino acid residues with conversative substitutions, which may have little or no effect on protein function, is known in the art (e.g.: French et al, 1983).
As a second aspect, the claims are directed to the treatment of any metabolic disorder in a subject (i.e.: claims 1, 6, 13-22, 24, and 74-75 generically recite “a metabolic disorder”) with a treatment that is an inhibitory nucleic acid molecule that hybridizes to a MAP3K15 nucleic acid molecule. It is not clear which of the particular mutations disclosed in the specification may actually provide a loss-of-function that is in fact associated with a decreased risk of any particular metabolic disease. The specification only discloses an aggregate analysis of mutation burden in a subject (e.g.: p.120-121 of the specification) associated with lower levels of hemoglobin A1c, lower serum glucose and protection from Type-2 diabetes. Thus, while the disclosure (p.120) asserts, for example, that “a burden of pLOFs and deleterious missense variants in MAP3K15 was also associated with protection from Type-2 diabetes”, the disclosure does not teach which of the broadly encompassed mutations are in fact identified in case subjects with any particular metabolic disease or control individuals without any particular metabolic disease, or with any phenotypes other than lower levels of hemoglobin A1c, lower serum glucose and protection from Type-2 diabetes.
Here it must also be noted the claims encompass a significantly large genus of any possible single or multiple nucleotide insertion, deletion or substitution in the coding or non-coding region of the MAP3K15 gene; and that the size of the genus is further compounded by the fact that the claims encompass detecting the MAP3K15 genetic variant in any subject, including non-human subjects.
However, the specification does not describe in terms of its complete structure or other relevant identifying characteristics a representative number of MAP3K15 mutations that cause a LOF, which also have the functional attribute that they are associated with decreased risk of any metabolic disease (related to the treatment of such generically encompassed disease with a MAP3K15 inhibitory nucleic acid).
It is acknowledged that the specification teaches the general methodology for sequencing and performing association studies. However, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
While the Federal Circuit has recognized that “the written description requirement can in some cases be satisfied by functional description,” it has made clear that “such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art.” In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004).
Herein, the claims recite a functional description of the MAP3K15 genetic variants but do not identify a clear structure-function relationship – i.e., do not disclose a clear structure of MAP3K15 variants that perform a function that results in the recited loss of function, or is a target for treatment of any metabolic disease.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112(a) as maintained above. Applicants’ arguments (p.8-10 of the Remarks of 12/05/2025) have been considered but are not persuasive to withdrawn the rejection. Relevant to the maintained rejection, Applicants have argued that the specification “discloses numerous MAP3K15 variant nucleic acid molecules”. This argument is not persuasive. The claims generically encompass any nucleic acid structures that are any variations in the MAP3K15 nucleic acid sequence. And while the specification teaches numerous particular mutations, the disclosure of these particular alterations is not informative of any other different variations that may be found in a sample from a subject. The nature of alleles is that they are variant structures occurring in genomes of individuals from a population; and in the present state of the art, the structure of one allele does not provide guidance to the existence or structure of any other alleles. The Examiner maintains, as set forth in the rejection, that the identification of any variation as generically encompassed by the claims as a loss-of-function variant is not adequately supported by the application as originally filed.
Additionally, as noted in the rejection, the disclosure of the application is not a teaching of the association MAP3K15 with any metabolic disorder (as generically encompassed by the claims), and is particular to levels of hemoglobin A1c, serum glucose and Type-2 diabetes. Here it can further be noted that the generically encompassed language of the claims (i.e.: treatment of any metabolic disorder) in combination with the particular required treatment (i.e.: inhibition of MAP3K15) is not supported by the particular disclosure of the application as originally filed because there exist a wide variety of pathologies related to metabolism, where it is not established that inhibition of MAP3K15 would be a suitable therapy for the broadly encompassed pathologies. For example, while the specification as filed may lead to the understanding that inhibition of MAP3K15 would treat pathology related to hemoglobin A1c, serum glucose and Type-2 diabetes, it is not established based on the application as filed that the same treatments would be suitable for Gaucher’s disease or hemochromatosis (see Kandola et al (2023) for a review of the disparate nature of different metabolic disorders).
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims under 35 U.S.C. 102(a)(1) as set forth on pages 14-15 of the Office Action of 09/11/2025, is withdrawn in light of the amendments to the claims.
Conclusion
Claims 1, 6, 13-22, 24, 31-35 and 74-75 are rejected.
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683