DETAILED ACTION
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 .
Application Status
Applicant’s response filed July 14, 2026 is acknowledged. Claims 1-13, and 28-35 are pending.
Restriction/Election
Applicant’s election of Group III (claims 28-31, and 35) in the reply filed on July 14, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-13, and 32-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 28-31, and 35 are under consideration hereinafter.
Priority
Applicant’s claim for priority to Application Nos. 63/431,755 and 63/432,592 is acknowledged. Claims 28-31, and 35 find support in Application No. 63/431,755, and therefore, the effective filing date of the claims under examination is December 12, 2022.
Drawings
The drawings are objected to because of the following informalities:
The drawings are objected to because they were submitted in color, but there is no granted petition to accept color drawings. See 37 CFR 1.84(a)(2) (“The Office will accept color drawings in utility patent applications only after granting a petition filed under this paragraph explaining why the color drawings are necessary”). Applicant must either provide that explanation via a petition and comply with all requirements of 37 CFR 1.84(a)(2)(i)-(iii) OR submit replacement sheets in black and white and include a clear instruction to replace the color drawings with the replacement sheet(s). The Examiner takes no position on whether color drawings are necessary as the only practical medium by which to disclose the subject matter sought to be patented in this utility patent application.
Appropriate correction is required.
Specification
The specification is objected to because of the following informalities:
The specification makes reference to color drawings. As described above, color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. No such petition has been filed or accepted in this application. Examiner recommends either I) removing the reference to color drawings, or alternatively, II) filing a petition to accept color drawings.
Appropriate correction is required.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Written Description
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 28-31, and 35 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.
MPEP 2163.II.A3.(a).(i) states the following:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. 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).”
Species Encompassed
The claims encompass an “HNF4A gain-of-function variant nucleic acid molecule” (hereinafter referred to as the “variant nucleic acid molecule”), encoding an HNF4α protein. The variant nucleic acid molecule may comprise a “splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, and/or an in-frame indel variant.” The claims also recite a variant nucleic acid molecule comprising “the genetic variation rs150776703.”
The specification does not appear to provide an explicit definition of “gain-of-function” or require that the “variant” be relative to any particular reference sequence (pg. 7). The specification does provide that the variant nucleic acid molecule may, for example, result in “increased expression or activity of HNF4A mRNA or polypeptide,” or “increased in vitro and in vivo response to HNF4A ligands” (pg. 6). The type of variation is virtually unlimited, and encompasses, as described above, variants comprising additional or fewer stop or start codons (“stop-gain,” “start-loss,” “stop-loss”), splice-site, frameshift, missense, and indel variation. The specification does not exclude variation in non-coding regions, or explicitly require that the variation be in a coding region (pg. 6). The variant nucleic acid molecule, therefore, may be a non-coding region variant, wherein the encoded HNF4α protein comprises a wildtype HNF4α protein sequence.
Together, the claims encompass a genus of variant nucleic acid molecules encoding an HNF4α protein, and comprising variation relative to any HNF4A reference sequence (e.g., non-coding, splice-site, stop- or start-loss/gain, indel, etc.) that results in increased expression and/or activity of HNF4A mRNA and/or polypeptide (i.e., “gain-of-function”). The specification has not sufficiently described the genus of HNF4A gain-of-function variant nucleic acid molecules encoding an HNF4α protein for the reasons that follow.
Species Described in the Specification
The specification describes a single variant nucleic acid molecule, set forth in SEQ ID NO: 2, and comprising variation relative to an HNF4A reference sequence, wherein the variation consists of “rs150776703,” which encodes a Pro437Ser HNF4α protein (pg. 8; pg. 36; pg. 38). The variation is a “rare missense variant,” which the specification states, “showed a protective association with Type 2 diabetes” and “chronic kidney disease” (pg. 38). The specification states that compared to transient transfection with wildtype nucleic acid molecule, transient transfection of cells with the variant nucleic acid molecule “appeared” to result in greater expression of HNF4α protein (pg. 40). The specification references Figs. 1B-C. Based on Fig. 1C, the skilled artisan would conclude that, indeed, slightly, but non-significantly more HNF4α protein is present following transient transfection with the variant nucleic acid molecule. The specification alleges that the results indicate that the variant nucleic acid molecule is “likely to be a gain of function mutation, due to increased stability, reduced degradation, or other post-translational modification” (pg. 40).
The specification does not provide any studies which evaluate the nature of the single variant nucleic acid molecule described therein. The specification’s evidence that the variant nucleic acid molecule is “gain-of-function” is limited, and amounts to a single experiment showing non-significant differences in protein levels following transient transfection. Thus, at best, the specification provides a single species in the claimed genus. The specification does not provide any other species within the genus, or provide any means to predict which of the many variant nucleic acid molecules comprising any variation, relative to any HNF4A reference sequence, will result in increased expression and/or activity of HNF4A mRNA and/or polypeptide (i.e., “gain-of-function”).
Species Described in the Prior Art
A search of the prior art uncovered several loss-of-function variants associated with disease, but did not uncover any species within the claimed genus. See, for example, Mohlke (Mohlke et al., 2005, Current Diabetes Report, 5:149-156) which describes HNF4A loss-of-function variants implicated in MODY and T2DM (pg. 152-153, Fig. 1). The prior art does provide some guidance regarding prediction of gain-of-function variants. Based on Reva (Reva et al., 2011, Nucleic Acids Research, Vol. 39, No. 17, e118, pg. 1-14) and Hecht (Hecht et al., 2015, BMC Genomics, 16(Suppl 8):S1, pg. 1-12), which teach methods aimed at improving prediction of functional consequences of protein mutations, the skilled artisan would conclude that while prior art methods could reasonably predict whether a particular mutation will impact protein structure and function in general, it is not possible to predict whether a variant will be “gain-of-function,” because such a designation is “often subjective” (Hecht, pg. 2, left col.), and “can result from a change in the specificity of particular protein-substrate interactions or a change in the specificity of interactions with regulatory proteins,” information which does not appear to be accounted for in the prior art predictive models. Indeed, Reva states that “direct prediction of a mutation’s impact on molecular function based on first principles is currently impossible for a number of reasons…” (pg. 2, left col.). Based on the prior art, without experimentation, it is not possible to predict which variation(s) will result in an HNF4A gain-of-function variant nucleic acid molecule which increases HNF4α protein levels.
Considering the large variation in the genus, the small percentage of species described in the specification (at best, one species), and the lack of predictability provided by the prior art or specification for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Claim Rejections - 35 USC § 112(a) – Enablement
Claims 28-31, and 35 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 enablement requirement. 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 test of enablement is whether one skilled in the art could make or use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor, but rather is a conclusion reached by weighing many factors. These factors were outlined in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
The claims are drawn to a method of increasing the protein level of Hepatocyte Nuclear Factor 4 Alpha (HNF4α) in a subject in need thereof, comprising administering “an HNF4α protein encoded by an HNF4A gain-of-function variant nucleic acid molecule” to the subject. The phrase “administering an HNF4α protein encoded by an HNF4A gain-of-function variant nucleic acid molecule,” is interpreted as administering an HNF4A gain-of-function variant nucleic acid molecule which encodes the HNF4α protein (which would thereby, by expressed in the subject).
The scope of HNF4A gain-of-function variant nucleic acid molecules encompassed by the claim is described in paragraph 10 above and applied hereinafter. As stated therein, the genus includes nucleic acid molecules encoding an HNF4α protein, and comprising variation relative to any HNF4A reference sequence (e.g., non-coding, splice-site, stop- or start-loss/gain, indel, etc.) that results in increased expression and/or activity of HNF4A mRNA and/or polypeptide (i.e., “gain-of-function”). The variation may be in a non-coding region, such that the encoded HNF4α protein comprises a wildtype HNF4α protein sequence.
Accordingly, enablement of the claims requires that one of ordinary skill in the art be able to increase the protein level of HNF4α in a subject by administering any one of a large genus of HNF4A gain-of-function variant nucleic acid molecules encoding an HNF4α protein, comprising variation relative to any HNF4A reference sequence (e.g., non-coding, splice-site, stop- or start-loss/gain, indel, etc.) that results in increased expression and/or activity of HNF4A mRNA and/or polypeptide.
Guidance in the Specification
The guidance in the specification is described above in paragraph 11 and applied hereinafter. As described therein, the specification describes a single variant nucleic acid molecule encoding a missense variant HNF4α protein. The specification demonstrates that transient transfection with the variant nucleic acid molecule results in slightly, but non-significantly more HNF4α protein (Fig. 1B-C). Based on Fig. 1C, the largest effects appear minimal (e.g., fold change of ~ 5 vs ~6 in “Nuc,” Fig. 1C), and possibly driven by outliers. Alone, this data does not provide reasonable confidence that the same results would be expected in different contexts, particularly in vivo.
The specification’s evidence that the variant nucleic acid molecule is “gain-of-function” is also limited, and amounts to the single experiment showing non-significant differences in protein levels following transient transfection. The specification describes correlation between disease outcome and presence of the variation in subjects, but does not describe any effect of administering the variant nucleic acid molecule to any subjects. The lack of working examples in subjects, coupled with the lack of evidence that the single variant nucleic acid molecule described in the specification is “gain-of-function,” or will increase HNF4α protein levels in different contexts, leads to significant unpredictability for the claimed methods. It is further noted that at present, the claims encompass any HNF4A gain-of-function variant nucleic acid molecule. The specification provides no support for any other embodiments of the claims, because there are no other species described in the specification, or which can be predicted based on the specification.
State of the Prior Art
A search of the prior art uncovered several loss-of-function variants (Mohlke, pg. 152-153, Fig. 1), but did not uncover any species of gain-of-function variants. The prior art does provide some guidance regarding gain-of-function variants, which is described above in paragraph 12 and applied hereinafter. Based on the prior art, without experimentation, it does not appear possible to predict which variation(s) will result in an HNF4A gain-of-function variant nucleic acid molecule which increases HNF4α protein levels.
The search also failed to uncover any working examples of the claimed methods. The prior art does describe various methods using HNF4A agonists (see for example, Veeriah et al., 27 January 2022, Cell Death and Disease (2022)13:89, pg. 1-10, and Huang et al., 2020, Molecular Therapy: Nucleic Acids, Vol. 19, pg. 361-370). However, the prior art HNF4A agonists have substantially different mechanisms of action than the variant nucleic acid molecule administered in the claimed methods. It is not evident that small molecule or oligonucleotide-based agonists provide any predictability for the instantly claimed methods, which employ any one of a large genus of uncharacterized HNF4A gain-of-function variant nucleic acid molecules, encoding any one of a large genus of uncharacterized HNF4α proteins. Indeed, based on Ko (Ko et al., 2019, Cell Reports, 26, pg. 2549-2557), the effects of even the known HNF4α proteins are not predictable, owing to various tissue- and isoform-level dependencies, and uncharacterized interactions amongst various HNF4α protein isoforms.
Level of Skill in the Art and Experimentation Required
The level of skill in the art is high, however, the amount of experimentation required to practice the claims is undue. Neither the specification nor prior art sufficiently describe the HNF4A gain-of-function variant nucleic acid molecules which are administered in the claimed methods, or provide any means to predict which of the many nucleic acid molecules encoding HNF4α protein, and comprising variation relative to an HNF4A reference sequence would be “gain-of-function” and increase HNF4α protein levels. Neither the specification nor prior art provide any working examples of the claimed method, and the experiments in the specification directed to the single variant nucleic acid molecule described therein fail to provide convincing evidence that the variant nucleic acid molecule will increase protein outside of an in vitro context. In order to practice the invention, the skilled artisan would need to develop the various HNF4A gain-of-function variant nucleic acid molecules encompassed by the claim through trial-and-error, and then, engage in additional unpredictable experimentation to determine which of the variant nucleic acid molecules result in increased HNF4α protein levels in vivo.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the lack of working examples of sufficient evidence to provide predictability for the claims in either the specification or prior art, it is the conclusion that undue experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JENNIFER A DUNSTON can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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