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 .
Claims 2-5, 7-10, 12, and 17-19 are cancelled.
Applicant’s election without traverse of Group I, SEQ ID NO: 1, in the reply filed on 21 July 2025 is re-acknowledged. SEQ ID NOS: 1 and 2 are deemed to be free from the prior art and are allowable. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between species of oligopeptides, as set forth in the Office action mailed on 05/21/2025, is hereby withdrawn.
Claims 1, 6, 11, and 13-16 are pending and under examination on the merits.
Priority
Applicant’s claim of priority to U.S. Patent Application No. 14/198,804, filed on March 6, 2014, which is a continuation of PCT Application No. PCT/US2012/053900, filed on September 6, 2012, which claims priority to U.S. Provisional Application No. 61/531,278, filed September 6, 2011, is acknowledged.
Withdrawn Objections/Rejections
The objection to claim 1 is withdrawn in light of the corrective amendment to the claim in the 12/01/2025 claim amendments. All objections or rejections to claims 2-5, 7-10, 12, and 17-19 are withdrawn as moot in light of the cancellation of the claims noted in the 12/01/2025 claim amendments. The rejections of claim 6 are withdrawn in light of the new claim scope resulting from the 12/01/2025 claim amendments. The rejections of the claims under 35 USC §102 are withdrawn as overcome by the narrowing claim amendments dated 12/01/2025. The objection to the drawings and rejection for failure to comply with sequence guidelines are withdrawn as addressed by the amendments to the sequence listing and to the specification, each dated 12/01/2025.
New-Claim Interpretation,
Only 1 of the variable positions of the general formula (i): WXPXW may be varied while retaining a sequence having at least 90% identify to either of SEQ ID NOS: 1 or 2, said SEQ ID NOs being 12 amino acids in length, each (see for example, the recitation of claim 1as currently amended).
New-Claim Objections
Claim 6 is objected to for its dependence from rejected base claim 1 but would be allowable if rewritten into independent form.
Maintained-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.
Written Description:
Claims 11 and 13-16 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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.
The claims are directed to an oligopeptide, a testing kit comprising the same, and a medical composition comprising the same. The oligopeptide is structurally defined as a genus wherein it comprises a binding motif of (i) WX1PX2W, wherein X1 and X2 can be any amino acid and having at least 90% identity with at least one of full-length amino acid sequences of SEQ ID NOs: 1 or 2. The oligopeptide is not defined in terms of length in the claims or in the specification. Thus, the structural limitations are nearly infinite, with only a requirement for one or two relatively small sequences. Functionally, the claims specifically require that the oligopeptide must bind collagen XII, bind cartilage tissue suffering from osteoarthritis, be useful in a testing kit therefor, or be useful in a medical composition therefor. In summary, the claims are directed to a genus that requires specific functions, but require only limited structural features.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claim is a partial structure in the form of one of two short consensus sequences. Regarding a diagnostic or medical activity as required by the claims, only oligopeptides C5-24 and C5-91 (SEQ ID NOs: 1 and 2, respectively) have been described as having functions in line with the functions required by the claims. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
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).
With the exception of SEQ ID NOs: 1 and 2, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only isolated oligopeptides comprising 100% identity to the amino acid sequences set forth in SEQ ID NOs: 1 and/or 2, but not the full breadth of the claim (allowing for 10% mutation within the sequence(s)) meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Scope of Enablement:
Claims 1, 11, and 13-16 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed invention wherein the recited oligopeptide comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, does not reasonably provide enablement for the claimed invention wherein the recited oligopeptide comprises variants of these sequences. 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 these claims. This is a rejection for partial lack of enablement.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
The claims are broadly drawn to oligopeptides, testing kits comprising the same, and medical compositions comprising the same. The specification indicates that these products bind collagen XII and can be used to target cartilage associated with osteoarthritis (OA) for delivery of diagnostic agents, lubrication supplements, and mesenchymal stem cells (MSCs) for repair purposes. Claims 11 and 13-16 specifically recite targeting of OA cartilage. While claims 1 and 6 do not explicitly recite such, since the specification only suggests how to use the recited oligopeptides to target OA cartilage, and thus the claims are interpreted as implying this activity limitation for the purposes of evaluation under 35 U.S.C. 112(a) regarding “how to make and use” corresponding to enablement.
The nature of the invention
The claims are directed to biological subject matter which is understood to be complex and often unpredictable. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology”, Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991).
The state of the prior art
The state of the prior art supports the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Tokuriki et al., 2009, Curr. Opin. Struc. Biol. 19:596-604). Fenton et al. (2020, Medicinal Chemistry Research 29:1133-1146) state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (2017, PLoS ONE 12(3): e0171355, https://doi.org/10.1371/journal.pone.0171355) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Alaoui-lsmaili (2009, Cytokine Growth Factor Rev. 20(5-6):501 -7) also indicate that designing a mutein having predictable activities is difficult:
Given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking, (page 502, right column, full paragraph 2).
Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (2004, PNAS USA 101(25):9205-10), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
The level of one of ordinary skill
As the claims are directed to oligopeptides, testing kits comprising the same, and medical compositions comprising the same, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
The state of the art supports the unpredictability of mutations within a peptide/protein primary sequence (See section (C) above). The state of the art further teaches that recombinant expression of complex mammalian proteins often results in inactive proteins due to improper folding and other post-translational processes. See Ulloa-Aguirre et al. (2004, Traffic 5:821-837) and Bernier et al. (2004, Curr. Opin. Pharmacol. 4:528-533). This is a serious problem in the recombinant production of mammalian proteins, as evidenced by Levy et al. (US 2014/0154743 A1; paragraph [0090]); and Chang et al. (U.S. 5,288,931; paragraph bridging col. 1-2). The primary amino acid sequence of a mammalian protein can have unpredictable effects on the ability of the protein to fold properly after recombinant expression. See Domingues et al. (U.S. 7,112,660 B2) and Sailer et al. (US 2003/0045474 A1). Therefore, making and using a peptide within the full scope of what is claimed would be expected to be unpredictable.
(F) The amount of direction provided by the inventor
In the instant case, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the oligopeptides which are tolerant to change (e.g. such as by amino acid substitutions, additions, or deletions), and the nature and extent of changes that can be made in these positions. Although the specification outlines art-recognized procedures for producing and screening for active muteins, this is not adequate guidance as to the nature of active derivatives that may be constructed but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore, substitution of non-essential residues can often destroy activity.
The existence of working examples
The specification provides detailed guidance and working examples as to how to make oligopeptides having structures commensurate in scope with the genus of oligopeptides. However, the specification only provides detailed guidance and working examples regarding how to use those oligopeptides having an activity profile consistent with uses in targeting OA cartilage. This sort of activity profile has only been established for oligopeptide clones C5-24 (SEQ ID NO: 1) and C5-91 (SEQ ID NO: 2).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Due to the large quantity of experimentation necessary to generate the infinite number of derivatives recited in the claims and possibly screen same for activity, the lack of direction/guidance presented in the specification regarding which structural features are required in order to provide activity, the absence of working examples directed to same, the complex nature of the invention, the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite any structural or functional limitations, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope. Only an oligopeptide having 100% identity to SEQ ID NO: 1 or SEQ ID NO: 2 are deemed to be enabled in view of the instant disclosure and the state of the art as of the effective filing date.
Applicant’s Arguments and Responses:
A. Applicant argues for withdrawal of the rejections for lack of written description (see pages 7-8 of 11 of the 12/01/2025 remarks). In summary, Applicant alleges that the claim amendment requiring the oligopeptide to have 90% identity to the full-length sequence of one of instant SEQ ID NOs: 1 or 2 brings the claim scope into alignment with what is described by the instant disclosure.
Response: Applicant does not provide an evidenced rationale for why the amended claims are adequately described. The statement that the requirement is met is merely conclusory. Only 2 examples of oligopeptides are described, an oligopeptide having 100% identity to SEQ ID NO: 1 and an oligopeptide having 100% identity to SEQ ID NO: 2. As can be seen, there are two points in the binding motif of general formula 1 which are represented by variable amino acids, though only one of which may be varied from SEQ ID NO: 1 or 2 in order to comprise a sequence having 90% identity to SEQ ID NO: 1 or 2. Where only 2 examples are given, it is unclear what residues (ALA, HIS, LEU, etc.) could be placed into position X21 and/or X2 of SEQ ID NO: 1 and/or 2 to form an oligopeptide which a viable/stable folding structure which may bind any target or exert any effect. As noted above, the state of the art supports a high degree of unpredictability. The narrowing amendment is appreciated, but 2 species is not deemed sufficiently representative of the breadth of claimed oligo peptides.
B. Applicant requests withdrawal of the rejections for partial lack of enablement (see pages 8-9 of 11 of the 12/01/2025 remarks). In summary, Applicant alleges that the claim amendment requiring the oligopeptide to have 90% identity to the full length sequence of one of instant SEQ ID NOs: 1 or 2 brings the claim scope into alignment with what is enabled by the instant disclosure because the artisan would have expected to achieve OA targeting.
Response: As noted in the response to the argument for withdrawal of the rejections for lack of written description above, Applicant merely asserts that the narrowing amendments narrow the claim scope to what is enabled. What Applicant has enabled in light of the instant disclosure is an oligopeptide having 100% identity to SEQ ID NO: 1 and an oligopeptide having 100% identity to SEQ ID NO: 2. There is no evidenced argument presented for the Examiner to consider regarding any alleged enablement of a broader scope. Applicant’s allegation that the artisan would have expected to achieve OA targeting with an oligopeptide having 90% identity to the full length sequence of one of instant SEQ ID NO: 1 or 2 is not supported by evidenced rationale, but is merely conclusory where no evidence is provided to rebut the unpredictability of the state of the art evidenced in the rejection for partial lack of enablement set forth above. The 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); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I).
Therefore, the rejections of record, as presented in this Office Action, are maintained at this time.
Conclusion
No claim is allowed.
Notice: An oligopeptide comprising a sequence having at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2 has been searched and is deemed to be free from the prior art. The closest prior at is WO 2014/160465-A2 (COUR PHARMACEUTICALS DEVELOPMENT COMPANY; published 02 October 2014; effectively filed 13 March 2013; hereinafter ‘465; as cited in the rejection of the claims under 35 USC §102 in the previous office action dated 09/05/2025) which teaches an oligopeptide with a structure comprising a variant of instant SEQ ID NO: 1, wherein the variant comprises a motif WX1PX2W (see alignment below).
INSTANT SEQ ID NO: 1: DLQYWYPIWDTH
|:||||:|
‘465 SEQ IS NO: 1224: TQGLKYWYPVWS
While the sequence of ‘465 shows the WXPXW binding motif, this motif is not disclosed to comprise or be paired with a sequence comprising a sequence with at least 90% identity to either of instant SEQ ID NOs: 1 or 2. Furthermore, the motif itself is not reasonably taught to be a conserved structure responsible for the function of binding collagen XII. Therefore, there is nothing in ‘465 alone, or in combination with the state of the prior art, to motivate the artisan to arrive at the claimed oligopeptide with any reasonable expectation of a given function/utility. It is noted that the primary structure of an oligopeptide is intolerant of mutations, such that any variation is unpredictable with regard to the effects on downstream structure (folding) and binding as supported by the references cited above in the rejection under 35 USC §112(a) for lack of written description and partial lack of enablement. Therefore, the instant claims are free of the prior art.
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 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 ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
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supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
