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 01/06/2026.
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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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.
Election/Restrictions
In the reply filed on 07/08/2025 Applicants elected the particular species that is a variant that is rs140312652 Asp182Asn (19:4159750:G:A).
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 101 and 102 are objected to and rejected over recitation of the phrase “according to GRCh38/hg38 assembly coordinates”, as recited in each claim. 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Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness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 rejections 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112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 2-3 of the Office Action of 10/07/2025, are withdrawn in light of the amendments to the claims.
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 10/07/2025, are 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
Claims 1, 7, 15-20, 36-41, 58 and 98-102 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 aspect it is noted that claims include methods of treating liver disease pathologies (i.e.: the claims generically encompass the treatment of any liver disease) comprising administering a CREB3L3 inhibitor that is an inhibitory nucleic acid which binds to a CREB3L3 nucleic acid molecule. However, the specification does not provide any actual treatments (e.g.: patient trials; animal models; cell models) in which a pathology is treated by administration of the required inhibitory nucleic acid molecule.
The lack of any working or exemplary model of the treatment (e.g.: amelioration of pathological symptoms) of a disease of liver disease in a subject with the required inhibitor is relevant where the related art teaches that lower levels of CREB-H (the protein encoded by the CREB3L3 gene) are associated with liver cancer (Chin et al (2005) cited on the IDS of 04/11/2023) and other liver-related pathologies such as fibrosis (Li et al (2020) cited on the IDS of 04/11/2023) and hyperlipidemia (Nakagawa et al (2015) cited on the IDS of 04/11/2023).
As a second aspect, the claims are drawn to methods that require detecting a CREB3L3 variant that is a loss-of-function mutation.
Relevant to the breadth of genetic structures encompassed by the claims, the specification (e.g.: p. 94) teaches that the variations may be frameshift, stop-gain, stop-loss, splice acceptor, splice donor, stop-lost, in-frame indel, missense, or other variants.
The specification further provides a table of CREB3L3 variants that can be used in an aggregate burden analysis, as set forth on pages 61-67.
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. For example, the elected alteration (rs140312652 (19:4159750:G:A, human genome build 38) in CREB3L3) encodes an Asp amino acid (reference) or an Asn amino acids (variant), but there is no evidence that the variant polypeptide in fact has lost any functionality.
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).
It is further 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 liver disease. The specification references (p.60) an aggregate analysis of mutation burden in a subject. Thus while the disclosure asserts an association between lower risk of liver disease and a burden of rare pLOFs, the disclosure only teaches an analysis of one particular variation (e.g.: p.91, Table 5) as overrepresented in subjects without liver disease.
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 CREB3L3 gene; and that the size of the genus is further compounded by the fact that the claims encompass detecting the CREB3L3 genetic variant in any subject, including non-human subjects (see for example p.6 of the specification as filed).
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 CREB3L3 genetic variants but do not identify a clear structure-function relationship – i.e., do not disclose a clear structure of CREB3L3 variants that perform a function that results in the decreased risk of liver disease.
With respect to the present invention, there is no record or description which would demonstrate conception of methods in which a liver disease (i.e.: in the breadth as generically encompassed by the claims which include any liver pathology in any subject organism) is treated using an inhibitors of CREB3L3, or a representative number of CREB3L3 variants that a loss of function mutations.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112(a) as maintained above. Applicants’ arguments (p.12-14 of the Remarks of 01/06/2026) have been considered but are not persuasive to withdrawn the rejection. Relevant to the maintained rejection, Applicants have argued that the specification “discloses numerous CREB3L3 variant nucleic acid molecules”. This argument is not persuasive. The claims generically encompass any nucleic acid structures that are any variations in the CREB3L3 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 of any particular CREB3L3 variation with any liver disease (as generically encompassed by the claims), where the disclosure teaches a specific association between rs140312652 and ALT levels (Table 3) or with the particular pathologies that are Parenchymal liver disease or NAFLD (Table 5). The related aggregate burden analysis related to ALT levels (Table 4) is of limited value to establish a written description of the claimed subject matter because this aggregate burden analysis fails to teach which particular mutations may be over-represented in a case or control subject. In this regard it is noted that when considering such analysis of biological analytes in case:control studies, the identification of a correlation is not the same as the identification of a cause such that a treatment can be established (e.g.: Richards (2020)).
Furthermore, as noted in the rejection, it is unclear that administration of an inhibitory nucleic acid that hybridizes to a CREB3L3 nucleic acid (e.g.: siRNA or shRNA to reduce the CREB3L3 gene product in a cell) would in fact have a treating effect related to any liver disease. As set forth in the rejection, the related art teaches that lower levels of CREB-H (the protein encoded by the CREB3L3 gene) are associated with liver cancer, and other liver-related pathologies such as fibrosis and hyperlipidemia. Similarly, the related art of Junli et al (2022) teaches that CREBH deficiency can exacerbated lipid metabolism disorders related to liver disease. As such the disclosure of the instant application (e.g.: related to genetic variations in the CREB3L3 gene asserted to be associated with phenotypes) is not a description of the treatment of those phenotypes, or any other liver diseases, by inhibition of the CREB3L3 gene.
Conclusion
No claim is allowed.
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
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