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 .
Status of Claims
Claims 1-3, 5-10, 12-15, 18, 20-22, 25-26, and 28 are currently pending and under examination.
Priority
Application claims priority to U.S. Provisional Application No. 63/002,467, filed March 31, 2020. Priority date of March 31, 2020 is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
Due to the US filing date before July 1, 2022, ST25 applies.
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 claim 10 is not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
Claim Objections
Claim 10 is objected because it fails sequence compliance. See above.
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.
1. Claims 1-3, 5-10, 12-15, 18, and 20-22 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 claims contain 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.
Claim 1 broadly encompasses an immunomodulatory chimeric molecule comprising human FGL2 FRED, “an immunomodulatory fragment or analog thereof,” and a half-life extending moiety. The Specification discloses full-length FRED (SEQ ID NO: 3), but defines fragments as encompassing as few as 50 amino acids and analogs as encompassing substitutions, deletions, or mutations, including sequences having as little as 60% homology to SEQ ID NO: 3, provided immunomodulatory activity is retained (paragraphs 0066 – 0068, pg. 4). However, the Specification does not disclose a representative number of such fragments and analogs throughout the claimed genus, nor sufficient structure-function relationships identifying which portions, substitutions, deletions, or mutations will retain the immunomodulatory activity. Accordingly, the disclosure does not reasonably convey to one skilled in the art that Applicant was in possession of the full scope of the claimed functional genus.
Claims 2-3, 5-10, 12-15, 18, and 20-22 depend from claim 1 but do not rectify these deficiencies.
2. Claims 1-3, 5-10, 12-15, 18, and 20-22 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 claims contain 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.
Considering the Wands factors in relation to claim 1:
1. The breadth of the claims is substantial because the claims encompass numerous FRED fragments and analogs combined with broadly defined half-life extending moieties;
2. The Specification provides working examples primarily for full-length FRED and particular HAS/Fc fusion constructs, rather than representative species across the claimed genus;
3. Although methods of making recombinant proteins and screening are known and described, the disclosure provides limited guidance for predicting which structural variants will possess the required function;
4. The art is biologically unpredictable, as demonstrated by Applicant’s own results showing that changes in fusion partner, orientation, and Fc configuration can substantially alter activity (Examples 9, 12, and 16); and
5. Determining operable species would require making and functionally screening potentially numerous variants using cytokine, proliferation, MLR, or maturation assays.
In particular, the Specification reports that some FRED-containing constructs expressed but lacked immune-regulatory activity, and that certain Fc-containing constructs showed no inhibition, poor inhibition, or even T-cell activation rather than immunosuppression (Table 1, Example 16). Thus, the quantity of experimentation needed to identify functional fragments, analogs, and fusion configurations across the full claimed scope would be more than routine optimization.
Claims 2-3, 5-10, 12-15, 18, and 20-22 depend from claim 1 but do not rectify these deficiencies.
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.
Claims 25-26, and 28 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.
Regarding claim 25, the claim recites administering “a pharmaceutical composition of claim 17.” However, claim 17 has been canceled and therefore does not presently define any pharmaceutical composition. Claim 18, rather than claim 17, is the pending claim directed to a pharmaceutical composition comprising the chimeric molecule of claim 1. Accordingly, the metes and bounds of the pharmaceutical composition required by claim 25 cannot be ascertained with reasonable certainty. Claims 26 and 28 depend from claim 25 but do not rectify these deficiencies.
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 (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 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, 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 for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 1-2, 5-9, 14-15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (European Journal of Immunology, 38(11): 3114-3126, 2013, cited on pg. 3 of IDS filed 07/24/2023) in view of Levy et al. (US7632495) and Rosen et al. (US20050054051).
Liu provides experimental proof of concept for immunomodulatory FGL2 fusion proteins in mice, including FcFGL2 and mouse-serum-albumin-FGL2 (MSA-FGL2), with the Fc or albumin moiety fused at the N-terminus of mouse FGL2 (Materials and Methods), and demonstrates retained FGL2 biological activity (Figs. 4, 6, and 7). Liu further teaches FGL2-mediated immunosuppression, including inhibition of dendritic-cell maturation and T-cell responses (Fig.6).
Liu differs from claim 1 in employing mouse rather than human FGL2. Levy teaches soluble FGL2 proteins from mammals including human FGL2, expressly claims human soluble FGL2 or fragments thereof (claim 8), and identifies “domain 2” as the FRED-containing C-terminal region responsible for immunomodulatory activity (claim 9). Therefore, it would have been obvious to one of ordinary skill in the art to employ the human FGL2/FRED-containing protein taught by Levy in Liu’s demonstrated FGL2 fusion-protein system to obtain the corresponding human immunomodulatory construct.
Levy and Liu do not expressly teach conjugating the immunomodulatory FGL2/FRED-derived molecule to a half-life-extending moiety. However, Rosen teaches fusion of therapeutic proteins, including fragments and therapeutic activity/half-life, and further teaches terminal fusion and use of intervening amino-acid linkers (paragraph 0257, pg. 60). It would have been obvious to one of ordinary skill in the art to modify the immunosuppressive FGL2/FRED-derived molecule of Levy/Liu by fusion to HSA as taught by Rosen in order to increase stability and prolong its useful circulating lifetime, with a reasonable expectation of obtaining a stabilized immunomodulatory fusion protein. Accordingly, claims 1 and 2 would have been obvious. Claim 2 is specifically met by Rosen’s HSA embodiment.
Regarding claims 5-6, Levy teaches immunosuppression through inhibition of T-cell proliferation and inhibition of dendritic-cell maturation (Summary, Figs. 3, 6-7), thereby rendering the recited immunosuppressive activity and immune-cell limitations obvious.
Regarding claims 7-9, Rosen teaches fusion of albumin and therapeutic proteins in terminal configurations and teaches intervening amino-acid linkers (paragraph 0271, pg. 61), making the claimed conjugation and linker arrangements obvious.
Regarding claims 14-15, Levy teaches recombinant FGL2 constructs produced using histidine-tag purification (column 17), such that inclusion of a conventional His tag would have been obvious for expression and purification of the claimed recombinant protein.
Regarding claim 18, Levy teaches pharmaceutical compositions containing soluble FGL2 for immune suppression, while Rosen teaches pharmaceutical compositions containing albumin fusion proteins. Therefore, a pharmaceutical composition comprising the obvious FGL2/HAS chimeric molecule and a pharmaceutically acceptable carrier would likewise have been obvious.
Claims 10 and 12 are further rejected under 35 U.S.C. 103 as being unpatentable over Levy/Liu/Rosen in view of Zhao et al. (Protein Expression and Purification, 61(1): 73-77, 2008). Zhao teaches insertion of the flexible amino-acid linker GGGGS between HAS and a therapeutic protein to reduce structural interference and improve stability (Abstract). It would have been obvious to employ Zhao’s known GGGGS linker in the HAS-FGL2/FRED fusion for the same predictable purpose. The GGGGS linker also necessarily does not comprise a sequence of at least 10 amino acids from FGL2, thereby satisfying claim 12.
Claims 20-22 are further rejected under 35 U.S.C. 103 over the foregoing references in view of Li et al. (Molecular Immunology, 117: 84-93, 2020). Li teaches the anti-inflammatory activity of FGL2 in an inflammatory-bowel-disease model, including attenuation of colitis, regulation of dendritic-cell maturation, and reduction of inflammatory signaling (Abstract). It would have been obvious to administer the Levy/Liu/Rosen FGL2 fusion composition to reduce inflammation and associated immune-cell/cytokine responses as recited in claims 20-22.
Conclusion
No claim is allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS GEORGE whose telephone number is (571)270-0340. The examiner can normally be reached M-F 8:30am - 5pm EST.
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, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DENNIS GEORGE/Examiner, Art Unit 1644
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights