CTFR 18/016,243 CTFR 82605 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 2. Applicant’s amendment filed on 01/27/2026 is acknowledged. 3. Claims 1-2, 8, 10-12, 17 and 19-20 are pending and under consideration. 4. The following rejections are necessitated by the amendment filed on 01/27/2026 . Claim Objections 07-29-01 AIA 5. Claim 17 is objected to because of the following informalities: claim 17 depends on cancelled claim 15 . Appropriate correction is required. Claim Rejections - 35 USC § 112 07-30-02 AIA 6. 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. 07-34-01 7. Claims 1, 8 and 20 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. Claim 1 recites: “A population of polypeptides, wherein the polypeptides comprise a sequence characterized as identical to residues 21-124 of SEQ ID NO:1; a PRE loop derived from SEQ ID NO:1 residues 1-20 replacinq residues 10- 19 with a randomized region from 1 to 10 amino acids; and comprising two cysteine residues that form a disulfide bond at residues 5 and 119.” SEQ ID NO:1 residues 1-124 are as follows (residues 1-20 are underlined): MKTK K LLIATVTLATGLLGI LPLTSMKLRVENPKKAQKHFVQNLNNVVFTNKELEDIYNLSNKEETKEVLKLFKLKVNQFYRHAFGIVNDYNGLLEYKEIFNMMFLKLSVVFDTQRKE A NNVEQ A. It is unclear what is meant by “residues 5 and 119” since this may refer to the residues of “the polypeptide” or the residues of SEQ ID NO:1. It is noted that the claim does not recite that residue 5 of SEQ ID NO:1 is included in “the polypeptide.” The numbering of the polypeptide and the numbering of SEQ ID NO:1 may be different since the polypeptide comprises “a PRE loop derived from SEQ ID NO:1 residues 1-20 replacinq residues 10- 19 with a randomized region from 1 to 10 amino acids.” B. The claim requires the polypeptide to comprise a sequence identical to residues 21-124 of SEQ ID NO:1 and residue 119 of SEQ ID NO:1 is not a cysteine. C. The claim requires the polypeptide to comprise a PRE loop derived from SEQ ID NO:1 residues 1-20 replacinq residues 10- 19 with a randomized region from 1 to 10 amino acids” and it is unclear whether the PRE loop does have residues 1-9 of SEQ ID NO:1. D. The claim requires the polypeptide to comprise a PRE loop derived from SEQ ID NO:1 residues 1-20 replacinq residues 10- 19 with a randomized region from 1 to 10 amino acids” and residue 5 of SEQ ID NO:1 is not a cysteine. E. Claim 20 recites that residues 12-16 “comprise” a sequence selected from any of SEQ ID Nos 17-40. Each of SEQ ID NOs 17-40 is 5 amino acids in length so residues 12-16 must necessarily consist of any one of SEQ ID NOs 17-40 and not “comprise” SEQ ID NOs 17-40 because they may not include additional amino acids. Correction is required. 07-36 AIA 8. The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA 9. Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 recites a single polypeptide and claim 1 upon which claim 8 depends is directed to a population of polypeptides. Claim 8 refers to particular features of claim 1 rather than claim 8 including all the limitations of the population of claim 1. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. 07-30-01 AIA 10. 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. 11. Claims 1 and 8 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 specification is enabled for : the polypeptides of SEQ ID NOs 1, 3, 5, 10-13, 16 and 41. The specification is not enabled for : population of polypeptides comprising the polypeptide as recited in claim 1. 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 or use the invention commensurate in scope with the claims. The specification disclosure does not enable one skilled in the art to practice the invention without an undue amount of experimentation. Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention. SEQ ID NO:1 residues 1-124 are as follows (residues 1-20 are underlined): MKTK K LLIATVTLATGLLGI LPLTSMKLRVENPKKAQKHFVQNLNNVVFTNKELEDIYNLSNKEETKEVLKLFKLKVNQFYRHAFGIVNDYNGLLEYKEIFNMMFLKLSVVFDTQRKE A NNVEQ The specification is not enabled for a polypeptide comprising a sequence identical to residues 21-124 of SEQ ID NO:1 wherein reside 119 is a cysteine because residue 119 of SEQ ID NO:1 is not a cysteine. Claim 1 requires the polypeptide to comprise a PRE loop derived from SEQ ID NO:1 residues 1-20 replacinq residues 10- 19 with a randomized region from 1 to 10 amino acids. One or ordinary skill in the art would be required to perform undue experimentation to make and use the invention commensurate in scope with the claims because there is no limiting definition in the specification for a PRE loop “derived” from SEQ ID NO:1 residues 1-20. The broadest reasonable interpretation of a derivative is any sequence which comprises a fragment of amino acids 1-20 of SEQ ID NO in addition to any number of additional amino acids. If the derivative comprises the first 10 amino acids of SEQ ID NO:1, residue 5 of SEQ ID NO:1 is not a cysteine. One of ordinary skill in the art would be required to perform undue experimentation to make and use the invention commensurate in scope with the claims. The specification does not adequately disclose how the skilled artisan would make and use the various polypeptides and complexes encompassed by the instant claims predictably for disclosed screening and therapeutic use. The claim recitations require undue experimentation to practice the claimed invention commensurate in scope with the claims. It is well established in the art that it is highly unpredictable which changes in amino acid sequence can be made in binding structures such that the derived polypeptide retains the ability to bind. Sailer et al. (PTO-892 mailed on 08/27/2025; Reference U) teaches that “proteins exist as ensembles of similar conformations. The effect of a mutation depends on the relative probabilities of conformations in the ensemble, which in turn, depend on the exact amino acid sequence of the protein. Accumulating substitutions alter the relative probabilities of conformations, thereby changing the effects of future mutations. This manifests itself as subtle but pervasive high-order epistasis. Uncertainty in the effect of each mutation accumulates and undermines prediction. Because conformational ensembles are an inevitable feature of proteins, this is likely universal” (In particular, abstract, whole document); and that “a key point from our work is that unpredictability can arise even in this extraordinary simple system. The problem of predicting evolution will only become harder as the complexity and realism of the models increase. Using a larger protein, for example, would increase the number of possible options and degeneracy of trajectories, making predictions more challenging.” (In particular, page 11942, left column, whole document). One of ordinary skill in the art could not predict which amino acids within the full length amino acid sequence of the recited genus of polypeptides could be substituted for which amino acids and whether the resulting polypeptide combinations exhibits requisite binding limitations. Predicting polypeptide structure from sequence data of a single amino acid sequence and attempting to utilize the predicted structural determinations to ascertain binding or functional aspects of any protein and what changes can be tolerated with respect thereto is complex and well outside the realm of routine experimentation. In re Fisher indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). As such, the claims are not enabled for the genus of polypeptides recited in the claims for predictable function to be used for screening and therapeutic use. One of ordinary skill in the art cannot use polypeptides with unpredictable functions. One of ordinary skill in the art would be required to practice undue experimentation to practice the invention commensurate in scope with the claims. In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed polypeptides, and complexes thereof. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. Without sufficient guidance, the changes which can be made in the instantly recited antibodies that maintains the functional properties of the antibodies of claim 4 is unpredictable; thus the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. 07-06 AIA 15-10-15 12. 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. 07-07-aia AIA 07-07 13. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA 14. Claim 2 is rejected under 35 U.S.C. 102( a)1 ) as being anticipated by U.S. Patent 5,639,869 (PTO-892; Reference A) as evidenced by the sequence alignment . U.S. Patent 5,639,869 teaches the polypeptide of SEQ ID NO:4 which comprises “an” amino acid sequence of SEQ ID NO:3 as evidenced by the following alignment. The term “an” opens the claim up to read on polypeptides comprising a fragment of instant SEQ ID NO:3. The reference teachings anticipate the claimed invention. PNG media_image1.png 723 671 media_image1.png Greyscale 15. Claims 10-12 and 19 appears to be in condition for allowance . 07-40 AIA 16. 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 extension fee 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 date of this final action. 17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (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 an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form. May 29, 2026 /Nora M Rooney/ Primary Examiner, Art Unit 1641 Application/Control Number: 18/016,243 Page 2 Art Unit: 1641 Application/Control Number: 18/016,243 Page 3 Art Unit: 1641 Application/Control Number: 18/016,243 Page 4 Art Unit: 1641 Application/Control Number: 18/016,243 Page 5 Art Unit: 1641 Application/Control Number: 18/016,243 Page 6 Art Unit: 1641 Application/Control Number: 18/016,243 Page 7 Art Unit: 1641 Application/Control Number: 18/016,243 Page 8 Art Unit: 1641 Application/Control Number: 18/016,243 Page 9 Art Unit: 1641 Application/Control Number: 18/016,243 Page 10 Art Unit: 1641
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