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 . 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 Nov, 2025 has been entered.
Election/Restrictions
Applicants elected group I (polypeptides) and SEQ ID 97 without traverse in the reply filed on 23 Sept, 2024. This sequence, and the Markush group containing it was determined to be novel and unobvious over the prior art in the office action of 26 Nov, 2024.
Claims Status
Claims 1-3, 7-10, 17-20, 22-25, 28-31, 34, 35, 37, 39, 50, 51, 53-55, 57, and 58 are pending.
Claims 1-3 have been amended.
Claims 53-55, 57, and 58 are allowable.
Claims 31, 34, 37, 39, 50, and 51 have been withdrawn due to an election/restriction requirement.
Maintained/Modified Objections
Claim Objections
Claims 28-30 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a)
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, 7-10, 17-20, 22-25, and 35 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would know which sequences are Kv1.3 inhibitors.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants appear to have tested about 6 dozen sequences that meet the claim limitations, all of which inhibit Kv1.3 (table 3, p61). There is no analysis of consensus sequences or of what portions of the sequence is required for activity, nor is there any discussion of what positions tolerate which modifications.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming sequences that inhibit the ion channel Kv1.3. This is a functional requirement that any sequence that meets the claim limitations must block this ion channel’s activity. However, applicants have not described the structure required to meet this functional limitation. A person of skill in the art would be unable to determine if a given sequence that meets the structural limitations of the claims also meets this functional limitation. In essence, applicants have made an important requirement defined by function. This is not sufficient to meet the written description requirement.
While there are a small number of amino acids held constant, this does not appear to be sufficient to give the claimed functional abilities. Winblade et al (US 20210171589) describe a number of sequences, including SEQ ID 224 (paragraph 29), that comprise the invariant amino acids of applicant’s sequences, but these are used to target cartilage (paragraph 35). While there is a boilerplate about adding or removing activities, such as binding to ion channels (paragraph 130), the authors clearly do not see this as the activity of the sequence –they explicitly discuss adding a compound with that activity (paragraph 167). In other words, the invariant amino acids in claim 1 are not sufficient to yield an ion channel antagonist.
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a biomolecule. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, several years after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants test about 70 different sequences. The claimed sequence allows for 9 substitutions, insertions, or deletions, where the substitution and deletions are limited to 32 of the 39 positions. This allows for 5x1054 possible sequences (assuming only natural amino acids and insertions that are only one amino acid, which are not claim limitations). Clearly, the sequences that applicants have described and tested cover only a very small percentage of the chemical space that they have claimed. Given that random mutations are often (and unpredictably) detrimental, without some information about what residues are important for activity (information that applicants have not presented), the sequences that applicants have described are not sufficient to provide written description for all that they have claimed.
response to applicant’s arguments
Applicants argue that each mutation has been validated, and that the core sequence selectively binds with high affinity.
Applicant's arguments filed 17 Nov, 2026 have been fully considered but they are not persuasive.
Applicants state that they have validated each mutation. However, the embodiments of the claims include sequences that vary greatly from what applicants have described in their specification. Given that the core sequence (C6, C12, C16, C27, N29, K31, C32, C34) is found in a sequence for an entirely different purpose, it is clear that the invariant residues are not sufficient to yield the activity required by the claims. While mutations are often additive, with high mutational loads, they can interact in more complex ways (Guo et al, PNAS (2004) 101(25) p9205-9210, p9207, 1st column, 3d paragraph); with the high mutational loading allowed by the claims, trying each mutation separately is not sufficient to provide written description. Should the number of allowable mutations be reduced such that the claimed subject matter more closely reflects the examples that applicants have data for, the rejection will be reconsidered.
Applicants argue that the core sequence binds strongly and selectively. However, applicants point to SEQ ID 1 for this. This appears to be a misunderstanding of how the term “core sequence” is used in the rejection. Applicants appear to believe it refers to the original unmodified sequence. However, it is intended to mean the non-variant portions of the original sequence, which is mostly just the Cys residues. The argument is not that there are no embodiments that comprise the core sequence that bind strongly and selectively, just that the claims cover embodiments that do not. The fact that the base sequence (which comprises the core sequence) has the required activity does not mean that other sequences comprising the core sequence will also have the activity.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658