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 .
DETAILED ACTION
The Amendment filed 7/8/2026 in response to Office Action of 4/8/2026, is acknowledged and has been entered. Claims 1, 3-4, 7, 10, 12-17, and 19-25 are now pending. Claims 20, 21, 23, 24, and 25 are amended.
The 112(b) rejection recited in office action dated 4/8/2026 is hereby withdrawn in view of amendments.
Claims 1, 3-4, 7, 10, 12-17, and 19-25 are currently being examined.
Maintained Rejections
(Arguments Addressed)
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 1, 3, 4, 7, 10, 12-17, and 19-25 remain 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 claims are drawn to a polypeptide comprising a variant of a member of a Sac7d that binds to human PD-L1 and inhibits binding of PD-L1 with PD1, wherein the variant comprises from 4 to 20 mutated residues located within an interface of binding of the member of the Sac7d family to its natural ligand, the mutated residues being selected from positions V2, K3, K5, K7, Y8, K9, G10, E14, T17, K21, K22, W24, V26, G27, K28, M29, S31, T33, D36, N37, G38, K39, T40, A44, S46, E47, K48, D49, A50 and P51 of Sac7d, wherein the variant comprises either:
Y8M, V26L, S31L, R42L, A44F substitutions or
Y8I, V26L, S31L, R42M, and A44L substitutions,
with numbering corresponding to SEQ ID NO: 1.
Thus, the claim is directed to any change of the residues as recited above, in any of the 30 positions listed above. It is unclear what the mutations will be, and unclear what residues can the residues be mutated to without disrupting the function. Thus, the claim is drawn to an unclear and partial structure, and lacks support for enablement.
The instant specification recites mutations known in the art and demonstrated in WO 2012/150314 and WO2008 068837. The instant specification discloses that the Sac7d protein family is described in WO 2008/068637. The instant specification discloses that WO 2012/150314 shows that mutations from one protein of the Sac7d family can be carried to another protein of the same family, and one can introduce the mutated amino acids of the Sac7d mutant within the scaffold of another protein, using the sequence alignment of figure 1. The instant specification discloses that in of the published specification that it is preferred when 7, 8,9, 10, 11, 12, 13 or 14 amino acids are mutated in the binding site of the OB-fold domain. [pgs 28-29 of the specification] The instant specification does not disclose what these specific mutations may be and still retain function. The instant specification does not demonstrate the mutations in all of the sites as recited the claim and whether it would function as claimed.
It is well understood in the art that mutations in amino acids can have structural and functional consequences, as taught by Sotomayor-Vivas et al (Linking protein structural and functional change to mutation using amino acid networks. PLoS One. 2022 Jan 21;17(1)). It is impossible to determine which residue(s) can be mutated for another residue, to still have the same effect and function. With regards to mutations in Sac7d, the Chen et al (Probing the DNA kink structure induced by the hyperthermophilic chromosomal protein Sac7d. Nucleic Acids Res. 2005 Jan 14;33(1):430-8) teaches that some mutations/amino acid substitutions have an effect on function of the protein. [pgs 436-437 Discussion]
Applicant is reminded that MPEP 2164.03 teaches “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 428 F.2d 833, 166 USPQ 18, 24 (CCPA 1970) the amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly state in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order for it to be enabling. Given lack of guidance in the specification, no one skilled in the art would accept the assertion that the claimed invention would function as contemplated or as claimed based only on the information in the specification and that known in the art at the time the invention was made.
The specification provides insufficient guidance with regard to these issues and provides no working examples which would provide guidance to one skilled in the art and no evidence has been provided which would allow one of skill in the art to predict that the invention will function as contemplated or claimed with a reasonable expectation of success. For the above reasons, it appears that undue experimentation would be required to practice the claimed invention
Response to Arguments
The applicants argue that the breadth of the claims is limited by the claim language. Applicants argue that although claim 1 covers a class of Sac7d variants, it does not cover arbitrary substitutions at arbitrary positions, and that claim 1 is confined by both structural and functional limitations. Applicant argues that structurally, the claim requires one of two specific substitution sets at positions 8, 26, 31, 42, and 44, and any additional variability is limited to a defined list of positions. Applicant argues that Functionally, the claimed variant must bind human PD-L1 and inhibit binding of PD-L1 to PD-1. Thus, the claim is directed to variants having specific, experimentally supported PD-L1-binding substitutions within a bounded Sac7d scaffold, not to an undefined universe of variants. Applicant argues that the specification provides numerous concrete working examples. Applicant argues that practicing the claimed invention would not require undue experimentation. Applicant argues the state of the art weighs in favor of enablement. The enablement rejection relies on general statements that amino acid substitutions may affect protein structure and function. Applicant argues that the Sac7d scaffold, the state of the art, the level of skill in the art, and the guidance in the specification provide sufficient direction to practice the claimed invention.
Applicant’s arguments have been considered but are not persuasive. The claim as written is drawn to: “a polypeptide comprising a variant of a member of a Sac7d that binds to human PD-L1 and inhibits binding of PD-L1 with PD1, wherein the variant comprises from 4 to 20 mutated residues located within an interface of binding of the member of the Sac7d family to its natural ligand, the mutated residues being selected from positions V2, K3, K5, K7, Y8, K9, G10, E14, T17, K21, K22, W24, V26, G27, K28, M29, S31, T33, D36, N37, G38, K39, T40, A44, S46, E47, K48, D49, A50 and P51 of Sac7d, wherein the variant comprises either: (a) Y8M, V26L, S31L, R42L, A44F substitutions or (b) Y8I, V26L, S31L, R42M, and A44L substitutions,
with numbering corresponding to SEQ ID NO: 1.
The claims are not structurally limited in terms of mutations, because it can comprise a mutation in any of these positions: V2, K3, K5, K7, Y8, K9, G10, E14, T17, K21, K22, W24, V26, G27, K28, M29, S31, T33, D36, N37, G38, K39, T40, A44, S46, E47, K48, D49, A50 and P51, as well as what is recited in (a) and (b)
It is unclear what the mutations will be, and unclear what residues can the residues be mutated to without disrupting the function. Contrary to Applicant’s arguments, the instant specification does not disclose what these specific mutations may be and still retain function. The instant specification does not demonstrate the mutations in all of the sites as recited the claim and whether it would function as claimed. The art also demonstrates that any mutations in any protein, including Sac7d, may have effects on the structure and mutation.
Claim 24 and 25 remain 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 cancer comprising administering the polypeptide of claim 1 as monotherapy, does not reasonably provide enablement for the combination of the polypeptide of claim 1 with a chemotherapy agent or a CAR T-cell The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF THE CLAIMS: Claims 24 and 25 recite that the peptide is administered in combination with chemotherapy or treatment with CAR T-cells.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification discloses the following: Example 3 demonstrates the comparison of an anti-HSP110 variant alone or combination with anti-PD-L1 variant. Example 4-6 demonstrates the efficacy of the variant in in vivo cancer models. None of the examples in the specification demonstrate the instantly claimed polypeptide in combination with either chemotherapy or treatment with a CAR T-cell.
STATE OF THE ART: It is well known that the art of anti-cancer therapy is highly unpredictable, for example, Gura (Science, 1997, 278:1041-1042) teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models that only 29 have actually been shown to be useful for chemotherapy See p. 1041, see 1st and 2nd para. Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Additionally, Chames et al (British J. of Pharmacology, 2009, 157, 220-233) teach that there are several challenges to development therapeutic antibodies. These challenges include functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system (Abstract). Additionally, Chames teaches several limitations of therapeutic antibodies such as affinity between the antibody and its antigen, competition with patient’s IgG, and efficiency issues in triggering the immune response (pages 224-225).
PREDICTABILITY: The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to treat cancer in combination with the instantly claimed combination with either chemotherapy and/or a CAR T-cell. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine claimed agent is administered with what agent to treat and prevent each disorder claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed agents treats cancer as claimed. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Response to Arguments
The applicants argue that claims 24 and 25 do not require the discovery of a new therapeutic principle or a new class of combination therapy. The Applicant argues that the recited combinations apply that checkpoint-blockade mechanism in combination with therapeutic modalities that were well established before the priority date. Applicant argues that by the priority date, combining anti-PD-1/PD-L1 checkpoint blockade with chemotherapy was a recognized therapeutic strategy. Applicant also argues that combining checkpoint blockade with CAR-T cell therapy was an actively pursued approach in the art. Applicant argues that a skilled artisan would have understood how to administer an anti-PD-L1 checkpoint inhibitor in combination with chemotherapy or CAR-T cell therapy using routine methods known in the art. Applicant argues that The claims do not require the skilled artisan to identify a new checkpoint pathway, develop a new chemotherapy, develop a new CAR-T cell, or discover a new therapeutic principle. Applicant argues that the cited references do not address the enablement of administering an already-disclosed anti-PD-L1 agent according to known combination-treatment modalities.
Applicant’s arguments have been considered but are not persuasive. The claims recite the peptide is administered in combination with chemotherapy or treatment with CAR T-cells. None of the examples in the instant specification demonstrate the instantly claimed polypeptide in combination with either chemotherapy or treatment with a CAR T-cell. The prior art demonstrates that anti-cancer therapy is highly unpredictable. While there are cases of combination, “chemotherapy” encompasses a vast array of drugs and CAR T-cells may encompass various targets. Each chemotherapeutic or each CAR T-cell differs at least in structure, activity, efficacy and side effect profile. The art cited above demonstrates the challenges of combining various anti-tumor drugs including, functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system. Additionally, the efficacy of the combination of the instantly claimed combination is not predictable, and there would be an undue amount of experimentation to assess the instantly claimed combination with every chemotherapeutic and every type of CAR T-cell.
Conclusion
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 SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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