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 .
Response to Amendment
Applicant’s amendment filed 30 September 2025 has been received and entered. Claims 27, 31-33, 36, 39-40, 45 and 47 have been amended and claims 1-26, 28-30, 37-38 and 48-78 have been canceled. Claims 27, 31-36 and 39-47 are currently pending.
Election/Restrictions
Applicant's election with traverse of the species of FGF21 variant having the amino acid sequence of SEQ ID NO:2 (L98R, S167H, P171A, R175L and R19V) in the reply filed on 06 December 2024 is acknowledged. The traversal is on the ground(s) that the subject matter of all the species is sufficiently related that a thorough search for the subject matter of any one species would encompass a search for the subject matter of the remaining species and therefore a search and examination of the entire application could be made without serious burden. This is not found persuasive because search burden is not a consideration for a Lack of Unity determination. The species were found to Lack Unity because the technical feature recited in the claims did not make a contribution over the prior art in view of CN111662373A. Furthermore, the different FGF21 polypeptides encompassed by the claims have distinct amino acid sequence structures and therefore, the various polypeptides do not share a common structural feature wherein the structural feature provides for a common function. Claim 27 is generic in that it encompasses FGF21 or “a variant thereof”. Depending on the variant, the FGF21 variant could have vastly different properties which would result in variants which do not have common uses (e.g. agonist vs. antagonist).
The requirement is still deemed proper and is therefore made FINAL.
Claims 30 and 31 will be examined in so far as they are directed to the elected species SEQ ID NO:2 (SEQ ID NO:1 with substitutions L98R, S167H, P171A, R175L and R19V).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 September 2025 has been considered by the examiner.
Drawings
The drawings were received on 30 September 2025. These drawings are not acceptable.
The drawings remain objected to because they do not comply with 37 CFR 1.84(a)(1) which requires the use of India ink, or its equivalent that “secures solid black lines”. The lines of the drawings are pixilated and therefore are not solid. This results in the lines, text and features appearing fuzzy and unreadable at times. Features of Figure 3 are still completely illegible.
Figures 1, 2 and 13 are photographs which do not comply with 37 CFR 1.84(b)(1). While the Office will accept photographs if they are the only practicable medium for illustrating the claimed invention, they “must be of sufficient quality so that all details in the photographs are reproducible in the printed patent”. The quality of the photographs which are currently present in the instant application do not meet this quality requirement. No details can be seen in Figure 13 and the supporting text and labels in Figures 1-2 are blurry.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Applicant asserts at page 7 of the response that replacement sheets have been submitted. Applicant’s arguments are not persuasive as the replacement sheets do not obviate the previously noted deficiencies.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The specification at [00100] beginning at page 17 and continuing onto page 18 references peptide linkers which are amino acid sequences. Sequence identifiers are required.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Response to Arguments
Applicant asserts that the specification has been amended to include sequence identifiers for the linker sequences disclosed on page 17 of the specification. Applicant’s argument has been fully considered, but is not found persuasive.
Applicant’s substitute specification has been received and entered. While the submission adds Sequence identifiers for some of the disclosed amino acid sequences found on page 17 of the specification, it does not provide a Sequence identifier for all of the disclosed amino acid sequences on this page. See screenshot below:
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“GGGS”, “GGGS”, and “GGGGGS” are all amino acid sequences which are encompassed by the Sequence rules and which require Sequence identifiers. See 37 CFR 1.831 (b)(1). Therefore, the instant application is still not in sequence compliance.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it does not reflect or include the subject matter to which the claims are directed. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant has not addressed the deficiencies noted above with regard to the title and abstract in the response filed 30 September 2025.
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.
Claims 27, 31-36 and 39-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating fatty liver-related diseases in a male patient in need thereof, does not reasonably provide enablement for the same method wherein the patient is female. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant claims are directed to methods of treating fatty liver-related diseases in a patient by administration of an FGF21 polypeptide (elected species having amino acid substitutions L98R, S167H, P171A, R175L and R19V compared to native FGF21 having the amino acid sequence of SEQ ID NO:1). The prior art of Fischer et al. (Endocrinol. 152: 2996-3004, 2011; cited in the instant specification) teaches that FGF21 has the ability to reduce free fatty acids. However, the experiments which were performed in Fischer et al. were limited to male mice.
Chaffin et al. (JCIinsight. 7(19): e155848, 2022) teaches that FGF21 administration in female mice does not result in reduced triglycerides as compared to male mice (see Figure 3A. Chaffin et al. conclude that the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system (see abstract and Figure 1E-1F). Chaffin et al. also concludes that “these finding may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease” (see abstract).
Based on the findings in the prior art, the instant claims are not enabled for treating fatty liver-related diseases in female subjects because female and male subjects do not respond to FGF21 administration in the same way. Male subjects demonstrate a reduction in triglycerides in response to FGF21 administration while female subjects do not as evidenced by Chaffin et al. The examples in the instant specification are limited to in vitro experiments (Examples 1-3) and in vivo experiments in male mice (Examples 4-11). Therefore, the instant application does not provide any evidence to contradict the findings of Chaffin et al. Therefore, the instant claims are not enabled for methods of treating fatty liver-related diseases in a female subject by the administration of an FGF21 variant as claimed, absent evidence to the contrary.
Response to Arguments
Applicant argues at page 8 of the response that the specification contains direction and guidance and working examples showing the effectiveness of FGF21 in treating fatty liver-related diseases and that additional experimentation “may be necessary to confirm the effectiveness in female patients” but this “experimentation would not rise to the level of undue experimentation” and that it would be “merely routine”.
Applicant’s argument has been fully considered, but are not found persuasive. As pointed out in the rejection above, Chaffin et al. teach that FGF21 administration in female mice does not result in reduced triglycerides as compared to male mice (see Figure 3A. While the instant application only used male mice, Chaffin et al. clearly examined the effect of administration of FGF21 (the protein of SEQ ID NO:1) and demonstrate that FGF21 administration in female mice does not reduce triglycerides. This is not an issue of more experimentation being necessary, but rather, a basic difference in how different patient populations respond to FGF21 administration. Chaffin et al. conclude that the benefit of FGF21 treatment for improving hepatosteatosis depends on sex and concludes that “these finding may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease” (see abstract). Therefore, based on the evidence of record, the claims are not enabled for their full scope for the reasons of record provided above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 27, 29-36 and 39-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 50-62 of copending Application No. 17/418,624 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed methods are obvious over the claims of ‘624. ‘624 claims an FGF21 variant with the amino acid sequence of SEQ ID NO:2, which has the substitutions L98R, S167H, P171A, R175L and R19V. The fusion protein constructs are the same as what are recited in the instant claims:
SEQ ID NO:2 (FGF21 variant) is the same as SEQ ID NO:2 in ‘624;
SEQ ID NO:13 (FGF21 variant fused to Fc) is the same as SEQ ID NO:17 of ‘624;
SEQ ID NO:19 (complete fusion of FGF21 variant, GLP-1 variant, linkers and Fc) is the same as SEQ ID NO:27 in ‘624.
‘624 claims a “method of treating diseases caused by FGF21 metabolic disorders” by administration of the FGF21 variant or fusions of the FGF21 variant. While ‘624 does not specifically recited treating “fatty liver-related diseases”, these diseases would be encompassed by “FGF21 metabolic disorders”. Furthermore, before the effective filing date of the instant claims, it was well-known that FGF21 was a treatment for fatty liver-related diseases as evidenced by Tucker et al. Therefore, the instant claims are not patentably distinct from those of ‘624.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues at page 11 of the response that the instant claims are not obvious variants of the claims of the ‘624 application because the claims of ‘624 are directed to proteins or immunoconjugates while the instant claims are directed to methods of treating fatty liver-related diseases. Applicant also asserts that while claim 62 of ‘624 recites a method of “treating diseases caused by FGF21 metabolic disorders” the claims of ‘624 do not recite treating fatty liver-related diseases and therefore, the instant claims would not have been obvious variants of the claims of ‘624.
Applicant’s arguments have been fully considered, but are not found persuasive. As pointed out in the rejection above, before the effective filing date of the instant claims, it was well-known that FGF21 was a treatment for fatty liver-related diseases. This fact is evidenced by Tucker et al. (cited in the previous Office action with regard to claim 27 prior to amendment) which teaches that administration of FGF21 can reverse steatosis, suppress hepatic and systemic inflammation and limit fibrosis in the liver among other things. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to administer the FGF21 variants of ‘624 in methods of treating fatty liver-related diseases as such diseases are FGF21 metabolic disorders. Because the prior art was keenly aware of the application of FGF21 for treating fatty liver-related diseases before the effective filing date, using the FGF21 variants of ‘624 in such methods would have been prima facie obvious, therefore, the instant claims are not patentably distinct from those of ‘624.
Citation of Prior Art
Keinicke et al. (FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation. Endocrine Connections 9: 755-768, 2020)
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 8am-4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, vanessa ford can be reached at 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Christine J Saoud/Primary Examiner, Art Unit 1645