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 .
Election/Restrictions
1. Applicant’s election without traverse of Group I, encompassing claims 1-14, and species election of SEQ ID NO: 3, in the reply filed on December 8, 2025 is acknowledged. Applicant states that claims 1-14 read upon the elected species.
2. Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 8, 2025.
3. It is noted that the motif sequences of SEQ ID NOs: 29-30 and 42-43 also read upon the elected SEQ ID NO: 3, in that they either comprise or are comprised by the sequence of SEQ ID NO: 3. Accordingly, claims 1-14, to the extent they are directed to the peptide of instant SEQ ID NOs: 3, 29-30 and 42-43, are under examination in the current office action.
Information Disclosure Statement
4. The information disclosure statement (IDS) filed 09/08/2022 has been considered and the references therein are of record.
Drawings
5. The drawings are objected to because the brief description of the figures for at least Figures 3A-3D, 5A-5C, 7A-7C, 9A-9D, 13C-1 and 13C-2 indicate that the figures use color (e.g., turquoise or maroon bars, red lines, etc.) Additionally, Figures 8D-8F are difficult to read because the print is small and faint. 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.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
6. Claims 6-8 are objected to because of the following informalities: claim 6 recites “SEQ ID Nos:28-61” and claims 7-8 recite “SEQ ID Nos28-61”, which are not consistent in their format within these claims nor are they consistent with the formatting of sequence identifier numbers in other claims. It is recommended the claims be amended to instead recite “SEQ ID NOs:28-61”. See also MPEP § 2422.01 V. Appropriate correction is required.
7. Applicant is advised that should claims 2, 6 and 9 be found allowable, claims 3, 7 and 10 will be objected to under 37 CFR 1.75 as being substantial duplicates thereof, respectively. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections – Improper Markush Grouping
8. Claims 1 and 6-10 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of peptides and nucleic acid molecules recited in the claims is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the ability to “modulate large conductance Ca+ activated K+ (BK) channel activity”, as stated in the specification, is not a common utility because a compound which inhibits BK channel activity and a compound which stimulates BK channel activity do not share a common utility (i.e., “modulation” encompasses both inhibition and activation of channel activity).
Further, there is no evidence that all peptides comprising the sequence CXXXXXXVC (SEQ ID NO: 27) share a common utility. The specification indicates that the peptides of the instant invention were isolated from a commercial monovalent phagemid library (see p. 66), stating:
With 6 randomized and 3 fixed amino acids, this library stated with 3 x 107 unique sequences. LS3 was selected as one of the sequences expressing motifs that were enriched more than 1000-fold.
Figures 3A and 3D of the instant specification show that some CXXXXXXVC peptides are stimulatory, some are inhibitory, and some appear to have no activity at all. Whereas the instant specification shows that all of the BK channel binding peptides identified therein share the motif CXXXXXXVC, there is no evidence that all, or even the majority of the peptides possessing this motif are capable of binding to a BK channel.
Because there appears to be no evidence that all peptide containing the CXXXXXXVC motif share a common utility, such as binding to, inhibiting or stimulating BK channel activity, wherein that activity is based solely upon the presence of that sequence motif, then this motif has not been demonstrated to serve as a common structural feature upon which a common utility is based.
With respect to the utility of shuttling a small cargo molecule across the blood-brain barrier (BBB) of a mammalian brain, the instant specification only attributes this activity to the LS3 peptide (SEQ ID NO: 3) (see p. 3). Further, the sequences CARGVYRVC (SEQ ID NO: 1) and CRVAHRAVC (SEQ ID NO: 2), for example, share no structural feature beyond the CXXXXXXVC motif sequence, and as indicated above, there appears to be no evidence of record to support the assertion that all peptides having the sequence CXXXXXXVC share a common specific and substantial utility.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use applicable to all compounds possessing that feature.
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.
9. Claims 1, 4-8 and 11-14 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. This is a written description rejection.
Claim 1 is drawn to a composition of matter selected from: (a) a peptide of SEQ ID NOs: 1-26 or a functional fragment or variant thereof; (b) a nucleic acid encoding the peptide of (a); an expression vector comprising the nucleic acid of (b); or a composition comprising the peptide of (a), nucleic acid of (b), or expression vector of (c), and a pharmaceutically acceptable carrier or diluent. Dependent claims recite that: the peptide comprises the formula CXXXXXXVC (SEQ ID NO: 27), wherein X is any natural or non-natural amino acid; the peptide comprises an amino acid sequence of any of SEQ ID NOs: 28-61, which sequences also contain X residues in which X is any natural or non-natural amino acid.
As discussed above, the instant specification does not provide a limiting definition for a “functional fragment” or a “variant” of the listed peptides, nor does is a specific function clearly defined. The specification indicates that the desired biological activity of the peptides is modulation of BK channel function (p. 32, lines 1-4), and that at least the LS3 peptide (SEQ ID NO: 3) is capable of suppressing BK channel activation and may also be capable of crossing the blood-brain barrier (Example 1). Yet it remains unclear that functional activities of the LS3 peptide are possessed by all of the other claimed peptides. The specification also indicates that the peptides of the invention can be used to produce antibodies that bind to the peptide (pp. 33-34).
Thus, the present claims encompass a genus of peptide fragments and variants having no or limited structural requirement and a broadly claimed function(s). The claims also encompass a genus of nucleic acid molecules that encode for the genus of structurally and functionally undefined peptides.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The factors to be considered when analyzing claims for compliance with the written description requirement include: actual reduction to practice; disclosure of drawings or structural chemical formulas; sufficient relevant identifying characteristics (e.g., disclosure of complete or partial structure, physical and/or chemical properties, structure/function correlation); method of making the claimed invention; level of skill and knowledge in the art; and predictability in the art. See MPEP §2163.
The recitation of a functional fragment or variant of a peptide of SEQ ID NOs: 1-26 represents a broad functional characteristic with limited to no structure. The compound’s structure can thus vary substantially within the given claimed recitations, particularly since the claims encompass not only peptides, but also nucleic acid molecules encoding the peptides as well as expression vectors comprising the nucleic acid molecules. The specification does not provide any limiting definitions for what a functional fragment or variant may be or comprise. The specification teaches that the variant and fragments can have any number of amino acid substitutions, additions, or deletions to the sequence of the peptide, as long as they retain substantially the same relevant biological activity as the peptides, such as modulation of BK channel function. Given this broad definition of what may constitute a fragment or variant, the genus of potential compounds is thus extremely broad.
The specification demonstrates that the peptides of SEQ ID NOs: 1-26 have variable and potentially opposing effects on BK channel functional activity (see, for example, Figures 3A-3D), which can be interpreted as the different peptides having suppressive, stimulatory or no activity on BK channel function. The specification teaches, for instance, that peptides LS15-18 (i.e., SEQ ID NOs: 15-18) “showed no significant effect”, and only half the tested peptides demonstrated any significant effect.
Moreover, the instant specification does not disclose structural features shared by members of the genus of peptides presently claimed. And given that peptides sharing similar motifs display variable functional effects (see, for instance Figs. 3A-3D and 11A-11C) the specification does not provide a definitive correlation between the structure of any disclosed peptide and the ability to suppress BK channel activity in order to establish possession of a genus of non-structurally defined peptides.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of peptide fragments, variants, or nucleic acid molecules encoding such fragments or variants, nor guidance as to which of the myriad of molecules encompassed by the claimed peptide fragments/variants/encoding nucleic acid molecules would meet the limitations of the claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the encompassed claimed compounds (if any) which have the ability to function as an functional fragment or variant of a peptide of one of SEQ ID NOs: 1-26 (or encoding nucleic acid molecules thereof) without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112(a).
Claim Rejections - 35 USC § 102
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 –
(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.
10. Claim(s) 1-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Scott et al. (“Finding novel BK channel modulators that alter ethanol behaviors” poster presented at WCAAR Advance (UT Austin), 2014, Austin TX; listed on IDS).
Scott et al. teach several novel peptides that were found by a high-throughput screening assay for BK channel modulators (pp. 7-8). These peptides include pskan3 (p. 11), pskan1 (p. 12), pskan6 (p. 14), and pskan4 (p. 16). Table 1 of the instant specification indicates that the peptide called pskan3 is also the instant SEQ ID NO: 3 (CRRGLVQVC; also called LS3), which addresses present claims 1-5 and 9-10. Further, the pskan3 peptide comprises the peptide fragments of XRGXXX (SEQ ID NO: 29) and RRXXXX (SEQ ID NO: 30), as in claims 6-7, as well as being a peptide that consists of the amino acid sequence of instant SEQ ID NO: 42 (CXRGXXXVC; wherein X is any amino acid) or SEQ ID NO: 43 (CRRXXXXVC; wherein X is any amino acid) as in claim 8. Further, according to Table 1 of the instant specification, the pskan1 peptide is instant SEQ ID NO: 1, pskan4 peptide is instant SEQ ID NO: 4, and pskan6 peptide is instant SEQ ID NO: 6. Note that the primary author of this publication (Scott, L.) is the same person as one of the instant inventors, and thus the pskan3 peptide of the Scott publication is reasoned to be the same as the instant peptide of SEQ ID NO: 3, absent evidence to the contrary.
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.
12. Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,183,972. Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass an isolated peptide comprising or consisting of the identical amino acid sequence CRRGLVQVC (SEQ ID NO: 3) (as well as CARGVYRVC (SEQ ID NO: 1) and CLQEQRGVC (SEQ ID NO: 11)). The patented ‘972 claims also recited that the peptide is a circular peptide having a disulfide bridge between the cysteine residues, the peptide further comprises a heterologous amino acid sequence, or other moiety, fused directly or indirectly to the amino acid sequence, wherein the moiety comprises a detectable label, and a pharmaceutical composition comprising the peptide and a pharmaceutically acceptable carrier or diluent. The peptide of SEQ ID NO: 3 of the patented claims also anticipates the generic formulas of at least SEQ ID NO: 42 (CXRGXXXVC) and SEQ ID NO: 43 (CRRXXXXVC) in present claims 6-10. The peptide of SEQ ID NO: 3 also comprises the motifs of instant SEQ ID NO: 29 (XRGXXX) and SEQ ID NO: 30 (RRXXXX) of instant claims 6-10.
Conclusion
13. No claims are allowed.
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. This art includes:
Yu M et al. Peptide toxins and small-molecule blockers of BK channels. Acta Pharmacologica Sinica (2016) 37:56-66. Yu et al. provide an overview of the structural and pharmacological properties of different BK channel blockers, including some venom peptide toxins from scorpions and snakes as well as several non-peptide blockers. Note that the short-chain peptide toxins comprise disulfide bridges between cysteine residues (Fig. 2).
Advisory Information
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675