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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7-24-2025 has been entered.
The amendment filed on 7-24-2025 is acknowledged. Claims 3-4 and 15 have been amended. Claims 5-6 and 8-12 have been canceled. Claims 2-4, 7 and 13-19 are pending.
Claim 13 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 2-4, 7 and 14-19 are currently under examination.
Information Disclosure Statement
The Information Disclosure Statement filed on 7-24-2025 has been considered. An initialed copy is attached hereto.
It should be noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections Withdrawn
The objection to claim for containing an obvious grammatical error is withdrawn in light of the amendment thereto.
The objection to claim 15 containing an obvious grammatical error is withdrawn in light of the amendment thereto.
Claim Objections Maintained
The objection to claim 15 for reciting claim language drawn to non-elected inventions is maintained for reasons of record as no generic claim is allowable. The elected invention is limited to the chimeric polypeptide comprising SEQ ID NO:8, SEQ ID NO:9 and a Pep-1 sequence (i.e. SEQ ID NO:17).
Claim Rejections Maintained
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.
The rejection of claims 2-4, 7 and 14-19 on the ground of nonstatutory double patenting as being unpatentable over claims 16 and 17 of U.S. Patent No. 11,773,145 is maintained for reasons of record.
Applicant argues
1. The amendment claims are drawn to fusion proteins wherein the cell penetration peptide is located to the N-terminus of the BoNT light chain or heavy chain whereas the cell penetration peptide of the patented claims is located on the C-terminus of the light or heavy chain.
Applicant’s argument has been fully considered and deemed non-persuasive.
With regard to Point 1, both claim sets still read on to methods of treating a malady (neurological disorders) by the administration of a chimeric polypeptide comprising a BoNT light chain, a BoNT heavy chain and a cell penetration peptide. While the patented claims do not explicitly recite the goal of “treating a condition” the only disclosed utility for the “administration” of said chimeric polypeptide is as a therapeutic. Moreover, the while the location of the penetrating peptide varies in the rejected claims they are clearly contemplated in the patent. Specifically, patented claim 3 clearly discloses the cell penetration peptide (zinc finger motif) being N-terminal to the BoNT light.
As outlined previously, although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to methods of treating a malady by the administration of a chimeric polypeptide comprising a BoNT light chain, a BoNT heavy chain and a cell penetration peptide. While the patented claims do not explicitly recite the goal of “treating a neurological condition” the only disclosed utility for the “administration” of said chimeric polypeptide is as a therapeutic.
The provisional rejection of claims 2-4, 7 and 14-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-11 and 25 of copending Application No. 18/557,232 (reference application) is maintained for reasons of record.
Applicant’s request to hold this rejection in abeyance is noted.
As outlined previously, although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to methods of treating a malady by the administration of a chimeric polypeptide comprising a BoNT light chain, a BoNT heavy chain and a cell penetration peptide. While the patented claims do not explicitly recite the goal of “treating a condition” the only disclosed utility for the “delivering” of said chimeric polypeptide is as a therapeutic. With regard to patented claims 7 and 8, they are deemed to constitute Product-by-Process type claims. In Product-by-Process type claims, the process of producing the product is given no patentable weight since it does not impart novelty to a product when the product is taught by the prior art. See In re Thorpe, 227 USPQ 964 (CAFC 1985); In re Marosi, 218 USPQ 289, 292-293 (CAFC 1983) and In re Brown, 173 USPQ 685 (CCPA 1972). Consequently, even if a particular process used to prepare a product is novel and unobvious over the prior art, the product per se, even when limited to the particular process, is unpatentable over the same product taught in by the prior art. See In re King, 107 F.2d 618, 620, 43 USPQ 400, 402 (CCPA 1939); In re Merz, 97 F.2d 599, 601, 38 USPQ 143-145 (CCPA 1938); In re Bergy, 563 F.2d 1031, 1035, 195 USPQ 344, 348 (CCPA 1977) vacated 438 US 902 (1978); and United States v. Ciba-Geigy Corp., 508 F. Supp. 1157, 1171, 211 USPQ 529, 543 (DNJ 1979). Finally, since the Patent Office does not have the facilities for examining and comparing Applicant' s composition with the compositions of the prior art reference, the burden is upon Applicant to show a distinction between the material, structural and functional characteristics of the claimed composition and the composition of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 2-4, 6-10 and 14-19 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. Cancellation of claims 6 and 8-12. 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.
Applicant argues:
1. It is well established in the art that the use of BoNTs includes neurological disorders.
2. Based on the well-known BoNT structure, the skill artisan would know where to make mutations on the BoNT/A light and heavy chains to have a 95% sequence identity to arrive at the claimed chimeric polypeptide.
3. Cell penetration peptides are well defined in the art.
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Points 1-3, the amendment is insufficient to overcome the rejection as there is still no correlation between structure (sequence) and function (i.e. to treat a given neurological disorder). While the skilled artisan might be able to envision BoNT light chains with at least 95% sequence identity to SEQ ID NO:8 and BoNT heavy chains with at least 95% sequence identity to SEQ ID NO:9, they would not be able to predict which of those variant chains would have efficacy (when coupled with a cell penetration peptide) to treat a given neurological disorder.
The instant claims are drawn the treatment of any and all neurological disorders (regardless of etiology) utilizing a chimeric polypeptide comprising (a) a botulinum toxin (BoNT) light chain having at least 95% sequence identity to SEQ ID NO:8, (b) a BoNT heavy chain having at least 95% sequence identity to SEQ ID NO:9, and (c) a cell penetration peptide located to the N-terminal of the BoNT light chain or located to the N-terminal to the BoNT heavy chain which is located C-terminal to the BoNT light chain or bound to the BoNT light chain through a the cell penetration peptide.
The claims are drawn to a vast genus of variant chimeric polypeptides which must have efficacy as a therapeutic for any and all neurological disorders. To fulfill the written description requirements set forth under U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the therapeutics for neurological disorders, Applicant must adequately describe the sequences of the component BoNT light chain, BoNT heavy chain and cell penetration peptide that combined into a single chimeric polypeptide elicit a therapeutic response against a given “neurological disorder”. The specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of chimeric polypeptides to which the claims are drawn, such as a correlation between the structure of the chimeric polypeptides and its recited function (inducing a therapeutic immune response against a given “neurological disorder”), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of therapeutics. Moreover, the specification fails to disclose which amino acid residues in said chimeric protein is essential for the induction of the claimed immune response or which amino acids might be added, replaced or deleted so that the resultant protein retains the immunological characteristics of its parent, or by which other amino acids the essential amino acids might be replaced so that the resultant protein retains the immunological characteristics of its parent. The art recognizes that defining epitopes is not easy and there is a confusing divergence between the textbook definition of epitope and the definition that is in use in published descriptions of experimental investigations and that epitopes must be empirically determined (Greenspan et al, Nature Biotechnology 17:936-937, 1999). Antibody epitopes are characterized by the art as either continuous or discontinuous (see pages 23-25, 27-33, Harlow et al, (Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press Inc., 1988). T cell epitopes are continuous peptide fragments of a polypeptide or antigen that have been processed by an accessory cell. Colman et al. (Research in Immunology 145: 33-36, 1994, p.33 column 2, p. 35 column 1) disclose that a single amino acid change in an antigen can effectively abolish the interaction with an antibody entirely and that a very conservative amino acid substitution may abolish antibody binding and a non-conservative amino substitution may have little effect in antibody binding. This underlies the importance of the description of the immunoepitopes that are therapeutic and which and where and how many changes can the immunoepitopes tolerate and still retain the ability to raise a given immune response. Even though one could screen for chimeric polypeptides that raise a therapeutic immune response against a given condition, the courts have held that possession of a genus may not be shown by merely describing how to obtain members of the claimed genus or how to identify their common structural features. The written description requirement is separate and distinct from the enablement requirement (See also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) and adequate written description requires more than a mere reference to a potential method for identifying candidate polypeptides. The purpose of the written description requirement is broader than to merely explain how to ‘make and use’ [the invention] Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991). The disclosure of only one member of the genus to which the claims are drawn is insufficient to describe the large and variant genus of proteins the scope of which is set forth above. In such an unpredictable art, as set forth supra, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Noelle v Lederman. 355 F. 3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) and In re Alonso (Fed. Cir. 2008-1079). Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of chimeric polypeptides to which claims refer; and accordingly, the specification fails to adequately describe at least a substantial number of members of the claimed genus of therapeutics for neurological disorders.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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 Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily have a given immunological property. The instant specification has failed to teach or disclose therapeutic compositions comprising the claimed chimeric proteins that are therapeutic against given “condition”. Consequently, there is no correlation between structure and function as required by the Written Description requirement.
Therefore, because the art is unpredictable, in accordance with the MPEP, the description of claimed vaccines is not deemed representative of the genus of therapeutics for neurological disorders to which the claim refers.
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.
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.
The rejection of claims 2-4, 7 and 14-19 under 35 U.S.C. 103 as being unpatentable over Dake et al. (WO 2005/084410 – IDS filed on 12-27-2023) and Kim et al. (Journal of Biochemistry and Molecular Biology Vol. 39 No. 5, pages 642-647 – IDS filed on 12-27-2023) is maintained for reasons of record.
Applicant argues:
1. Both Dake and Kim teach away from the claimed invention as they disclose that their light chains, heavy chains and CPPs are attached non-covalently.
2. Kim’s chimeric protein contained only the BoNT light chain while the instant claims require both the light and heavy chains.
3. Besides the effect of zinc finger motif, the present specification also discloses that the N- terminal TAT and Pep-1 fused full-size BoNT can be expressed and purified (FIG. 2, panel A and Example 1, paras. [0051] and [0101] of the specification as filed). These fusion proteins also show efficient cell penetration capabilities and protease activity in vitro and in vivo conditions. For example, the N-terminal ZFP and PEP-1 fused full-size BoNTs (Protein ID:3 and Protein ID: 8) in FIG. 3 showed higher in vitro activity of cell-penetrating BoNTA proteins than the wild type BoNTA (Protein ID: 1).
4. Liu et al. (2022), published by the inventor of the present application in 2022 (Front Bioeng Biotechnol. 2022 Feb 11:10:828427, submitted in the response to the non-final office action dated August 15, 2024), can be considered as a post-filing evidence which discloses that
the N-terminal TAT and Pep-1 fused full-size BoNTA exhibited higher in vitro protease activity of BoNTA than the wild-type BoNTA (Figure 1C).
Applicant’s arguments have been fully considered and deemed non-persuasive.
In response to applicant's argument that the references fail to show certain features of the invention (Point 1), it is noted that the features upon which applicant relies (i.e., that the heavy chain, light chain and CPP be covalently linked) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
With regard to Point 2, contrary to Applicant’s assertion, Kim et al. clearly disclose that their BoNT/A comprises a heavy chain and a light chain linked via non-covalent interactions and a disulfide bond (which is essential for neurotoxicity) [see page 642]. Moreover, the BoNT of Dake et al. comprises both heavy and light chains. Finally, Applicant is reminded that the rejection is based on the combination of the cited references and that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With regard to Points 3 and 4, as set forth in MPEP 7.16.02(d):
“Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Given the instant claims are drawn to the in vivo treatment of any and all neurological disorders regard of their etiology, Applicant has failed to provide evidence supporting their assertion of unexpected results. The MPEP states:
716.02(b) Burden on ApplicantBURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTEDAND SIGNIFICANTThe evidence relied up should establish “that the differences in results are in factunexpected and unobvious and of both statistical and practical significance.” Ex parteGelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions inappellants’ brief that the claimed polymer had an unexpectedly increased impact strength“are not entitled to the weight of conclusions accompanying the evidence, either in thespecification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. &Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybeanplant, however there was no basis for judging the practical significance of data withregard to maturity date, flowering date, flower color, or height of the plant.). See also Inre Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re EliLilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP §716.02(c).APPLICANTS HAVE BURDEN OF EXPLAINING PROFFERED DATA“[A]ppellants have the burden of explaining the data in any declaration they proffer asevidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat.App. & Inter. 1992).DIRECT AND INDIRECT COMPARATIVE TESTS ARE PROBATIVE OFNONOBVIOUSNESSEvidence of unexpected properties may be in the form of a direct or indirect comparisonof the claimed invention with the closest prior art which is commensurate in scope with theclaims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP §716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294,298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433(CCPA 1971) for examples of cases where indirect comparative testing was foundsufficient to rebut a prima facie case of obviousness.The patentability of an intermediate may be established by unexpected properties of anend product “when one of ordinary skill in the art would reasonably ascribe to a claimedintermediate the contributing cause’ for such an unexpectedly superior activity orproperty.” In re Magerlein, 602 F.2d 366, 373, 202 USPQ 473, 479 (CCPA 1979).“In order to establish that the claimed intermediate is a contributing cause’ of theunexpectedly superior activity or property of an end product, an applicant must identifythe cause of the unexpectedly superior activity or property (compared to the prior art) inthe end product and establish a nexus for that cause between the intermediate and the endproduct.” Id. at 479.
Additionally,
716.01(c) Probative Value of Objective EvidenceTO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULDBE SUPPORTED BY ACTUAL PROOFObjective evidence which must be factually supported by an appropriate affidavit ordeclaration to be of probative value includes evidence of unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before the dateof the reference, and allegations that the author(s) of the prior art derived the disclosedsubject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699,705, 222 USPQ 191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected resultsmust be established by factual evidence.” “[A]ppellants have not presented anyexperimental data showing that prior heat-shrinkable articles split. Due to the absence oftests comparing appellant’s heat shrinkable articles with those of the closest prior art, weconclude that appellant’s assertions of unexpected results constitute mere argument.”). Seealso In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parteGeorge, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCEThe arguments of counsel cannot take the place of evidence in the record. In re Schulze,346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorneystatements which are not evidence and which must be supported by an appropriateaffidavit or declaration include statements regarding unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before thedate of the reference, and allegations that the author(s) of the prior art derived thedisclosed subject matter from the applicant.
As outlined previously, Dake et al. disclose fusion proteins comprising BoNT and a carrier to for the reduction of muscle paralysis and other conditions (see abstract). Dake et al. further disclose that said fusions are administered to the subject’s skin or epithelium (see abstract) and that the BoNT can be any know types of botulinum toxins including A, B, C, D, E, F and G and subtypes thereof (see paragraph [0042].
Dake et al. differs from the claimed invention in that they don’t disclose the use of the PEP-1 peptide or the topical use on a stratum corneum of a skin that has been disrupted.
Kim et al. disclose fusion proteins comprising BoNT/A and a PEP-1 peptide that have been formulated for application to skin (see abstract for example). Kim et al. further disclose that the BoNT/A comprises a heavy chain and a light chain linked via non-covalent interactions and a disulfide bond (which is essential for neurotoxicity) [see page 642]. Finally, Kim et al. disclose that their PEP-1-BoNT/A is able to penetrate animal skin and can provide a new strategy for protein therapy of various disorders (see page 646). With regard to the sequence recited in claim 14, it is deemed that said sequence the PEP-1-BoNT/A of Kim et al. would necessarily have said sequence as it is the same chimeric molecule engendered by said claim.
It would have been obvious for one of ordinary skill in the art to utilize the PEP-1 peptide of Kim et al. with the BoNT/A toxin of Dake et al. in order to take advantage of the increased ability of fusions comprising of the PEP-1 peptide to deliver proteins to mammalian cells.
One would have had a reasonable expectation of success as Kim et al. disclose the use of the PEP-1 peptide with the BoNT/A light chain.
With regard to claim 17, the KSR decision sets forth “if a technique has been used to improve one device, and a person of skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill”. Given that Kim et al. demonstrates that their PEP-1-BoNT/A provides a new strategy for protein therapy and the various routes of administering botulinum toxins is well established in the art, the topical administration of a botulinum composition on a stratum corneum of a skin that has been disrupted is within the capabilities of one of ordinary skill in the art. Hence, the requirements of obviousness under the KSR decision are met.
The rejection of claims 2-4, 7 and 14-19 under 35 U.S.C. 103 as being unpatentable over Dake et al. (WO 2005/084410 – IDS filed on 12-27-2023) and Morris et al. (Nature Biotechnology, Vol. 19, pages 1173-1176) is maintained for reasons of record.
Applicant argues:
1. Dake teaches away from the claimed invention as they disclose that their light chains, heavy chains and CPPs are attached non-covalently.
2. Besides the effect of zinc finger motif, the present specification also discloses that the N- terminal TAT and Pep-1 fused full-size BoNT can be expressed and purified (FIG. 2, panel A and Example 1, paras. [0051] and [0101] of the specification as filed). These fusion proteins also show efficient cell penetration capabilities and protease activity in vitro and in vivo conditions. For example, the N-terminal ZFP and PEP-1 fused full-size BoNTs (Protein ID:3 and Protein ID: 8) in FIG. 3 showed higher in vitro activity of cell-penetrating BoNTA proteins than the wild type BoNTA (Protein ID: 1).
3. Liu et al. (2022), published by the inventor of the present application in 2022 (Front Bioeng Biotechnol. 2022 Feb 11:10:828427, submitted in the response to the non-final office action dated August 15, 2024), can be considered as a post-filing evidence which discloses that
the N-terminal TAT and Pep-1 fused full-size BoNTA exhibited higher in vitro protease activity of BoNTA than the wild-type BoNTA (Figure 1C).
Applicant’s arguments have been fully considered and deemed non-persuasive.
In response to applicant's argument that the references fail to show certain features of the invention (Point 1), it is noted that the features upon which applicant relies (i.e., that the heavy chain, light chain and CPP be covalently linked) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
With regard to Points 2 and 3, as set forth in MPEP 7.16.02(d):
“Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Given the instant claims are drawn to the in vivo treatment of any and all neurological disorders regard of their etiology, Applicant has failed to provide evidence supporting their assertion of unexpected results. The MPEP states:
716.02(b) Burden on ApplicantBURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTEDAND SIGNIFICANTThe evidence relied up should establish “that the differences in results are in factunexpected and unobvious and of both statistical and practical significance.” Ex parteGelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions inappellants’ brief that the claimed polymer had an unexpectedly increased impact strength“are not entitled to the weight of conclusions accompanying the evidence, either in thespecification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. &Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybeanplant, however there was no basis for judging the practical significance of data withregard to maturity date, flowering date, flower color, or height of the plant.). See also Inre Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re EliLilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP §716.02(c).APPLICANTS HAVE BURDEN OF EXPLAINING PROFFERED DATA“[A]ppellants have the burden of explaining the data in any declaration they proffer asevidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat.App. & Inter. 1992).DIRECT AND INDIRECT COMPARATIVE TESTS ARE PROBATIVE OFNONOBVIOUSNESSEvidence of unexpected properties may be in the form of a direct or indirect comparisonof the claimed invention with the closest prior art which is commensurate in scope with theclaims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP §716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294,298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433(CCPA 1971) for examples of cases where indirect comparative testing was foundsufficient to rebut a prima facie case of obviousness.The patentability of an intermediate may be established by unexpected properties of anend product “when one of ordinary skill in the art would reasonably ascribe to a claimedintermediate the contributing cause’ for such an unexpectedly superior activity orproperty.” In re Magerlein, 602 F.2d 366, 373, 202 USPQ 473, 479 (CCPA 1979).“In order to establish that the claimed intermediate is a contributing cause’ of theunexpectedly superior activity or property of an end product, an applicant must identifythe cause of the unexpectedly superior activity or property (compared to the prior art) inthe end product and establish a nexus for that cause between the intermediate and the endproduct.” Id. at 479.
Additionally,
716.01(c) Probative Value of Objective EvidenceTO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULDBE SUPPORTED BY ACTUAL PROOFObjective evidence which must be factually supported by an appropriate affidavit ordeclaration to be of probative value includes evidence of unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before the dateof the reference, and allegations that the author(s) of the prior art derived the disclosedsubject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699,705, 222 USPQ 191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected resultsmust be established by factual evidence.” “[A]ppellants have not presented anyexperimental data showing that prior heat-shrinkable articles split. Due to the absence oftests comparing appellant’s heat shrinkable articles with those of the closest prior art, weconclude that appellant’s assertions of unexpected results constitute mere argument.”). Seealso In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parteGeorge, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCEThe arguments of counsel cannot take the place of evidence in the record. In re Schulze,346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorneystatements which are not evidence and which must be supported by an appropriateaffidavit or declaration include statements regarding unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before thedate of the reference, and allegations that the author(s) of the prior art derived thedisclosed subject matter from the applicant.
As outlined previously, Dake et al. disclose fusion proteins comprising BoNT and a carrier to for the reduction of muscle paralysis and other conditions (see abstract). Dake et al. further disclose that said fusions are administered to the subject’s skin or epithelium (see abstract) and that the BoNT can be any know types of botulinum toxins including A, B, C, D, E, F and G and subtypes thereof (see paragraph [0042].
Dake et al. differs from the claimed invention in that they don’t disclose the use of the PEP-1 peptide or the topical use on a stratum corneum of a skin that has been disrupted.
Morrris et al. disclose fusions comprising the Pep-1 peptide. Morris et al. further disclose that the Pep-1 peptide is able to efficiently deliver a variety of peptides and proteins into several cell lines in a fully biologically active form, without the need for prior chemical covalent coupling or denaturation steps. In addition, this peptide carrier presents several advantages for protein therapy, including stability in physiological buffer, lack of toxicity, and lack of sensitivity to serum and that Pep-1 technology should be extremely useful for targeting specific protein–protein interactions in living cells and for screening novel therapeutic proteins (see abstract).
It would have been obvious for one of ordinary skill in the art to utilize the Pep-1 peptide of Morris et al. with the BoNT/A toxin of Dake et al. in order to take advantage of the increased ability of fusions comprising of the PEP-1 peptide to deliver proteins to mammalian cells.
One would have had a reasonable expectation of success as Morris et al. disclose the use of the PEP-1 peptide with the variety of differing proteins.
With regard to claim 17, the KSR decision sets forth “if a technique has been used to improve one device, and a person of skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill”. Given that Kim et al. demonstrates that their PEP-1-BoNT/A provides a new strategy for protein therapy and the various routes of administering botulinum toxins is well established in the art, the topical administration of a botulinum composition on a stratum corneum of a skin that has been disrupted is within the capabilities of one of ordinary skill in the art. Hence, the requirements of obviousness under the KSR decision are met.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT A ZEMAN whose telephone number is (571)272-0866. The examiner can normally be reached Monday thru Friday; 6:30 am - 3pm 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, Heather Calamita can be reached on 571-272-2876. 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.
/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 June 22, 2026
Prosecution Insights