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 .
The amendments and remarks filed 12/11/25 are acknowledged. Claims 11-15 have been amended. Claims 1-15 are pending.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 7/25/25.
Claims 11-15 are under examination.
Withdrawn Rejections
The rejection of claim 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in light of Applicant’s amendment thereto. See paragraph 8, page 10 of the previous Office action.
The rejection of claims 11-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hales (WO2017199014 A1, published November 23, 2017) in view of Chakrabarti et al. (J. Neurochem. 2016 Dec;139(5):737-747), is withdrawn in light of Applicant’s persuasive arguments. Specifically, the specification demonstrates that the combination of CSD polypeptides with c-SRC inhibitor PP2 provide enhanced prevention of morphine-induced analgesic tolerance not observed with either agent alone. See paragraph 13, page 12 of the previous Office action.
Maintained Rejections
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 11-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a method for preventing and/or reducing opioid analgesic tolerance in a subject with chronic pain comprising: administering to the subject an effective amount of: a caveolin-1 scaffolding domain (CSD) polypeptide having at least 90% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2 wherein said polypeptide is a full-length or biologically active fragment capable of reducing opioid analgesic tolerance; and jj) a non-receptor tyrosine kinase (c-Src) inhibitor, selected from the group consisting of dasatinib, PP2, and pharmaceutically acceptable salts thereof, wherein the subject is undergoing chronic opioid analgesic therapy prior to or concurrently with the administration of the CSD polypeptide and the c-Src inhibitor, and wherein said administration of the CSD polypeptide and the c-Src inhibitor prevents or reduces opioid analgesic tolerance in the subject.
Claim 15 is drawn to a method of treating, ameliorating, or preventing one or more symptoms of pain in a subject in need thereof, comprising: administering a therapeutically effective amount of an opioid analgesic to a subject; and administering a therapeutically effective amount of both a caveolin-1 scaffolding domain (CSD) polypeptide having at least 90% sequence identity to SEQ ID NO: 1, or SEQ ID NO: 2, wherein said polypeptide is a full-length or biologically active fragment capable of reducing opioid analgesic tolerance; and a c-Src inhibitor selected from the group consisting of dasatinib, PP2, and pharmaceutically acceptable salts thereof, wherein the administration of the CSD polypeptide and c-Src inhibitor reduces or prevents opioid analgesic tolerance and treats one or more symptoms of chronic pain selected from the group consisting of hyperalgesia, allodynia, and spontaneous pain.
The specification teaches that the CSD polypeptide refers to a cell permeable polypeptide capable of disrupting caveolin-1 signaling or scaffolding. The specification teaches that the CSD polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, combinations thereof, and/or functional fragments thereof. The specification teaches that the CSD polypeptide is highly related to the amino acid sequence of SEQ ID NO: 1 and has e.g., at least 90%, 95%, 97% or 99% sequence identity to SEQ ID NO: 1. The specification teaches that the CSD polypeptide is highly related to the amino acid sequence of SEQ ID NO:2 and has e.g., at least 90%, 95%, 97% or 99% sequence identity to SEQ ID NO: 2. The specification teaches that the term “c-Src inhibitor” means a compound that inhibits c-Scr and optionally one more members of the Src family kinase member such as c-Src. The specification teaches that preferably, the term c-Src inhibitor refers to a compound which is an inhibitor of c-Src, and is preferably a selective inhibitor of c-Src.
Regarding the CSD polypeptide, although the claims are inclusive of the CSD polypeptides having the amino acid sequence set forth in SEQ ID NO: 1 and SEQ ID NO: 2, the claims are not limited to SEQ ID NO: 1 and SEQ ID NO: 2. The claims broadly encompass polypeptides having at least 90% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2. This would represent a large pool of variant polypeptides that must have similar functional activity. A 10% variance, for example, in the CSD polypeptide set forth in SEQ ID NO: 1 that is 36 amino acids in length translates into 3 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 36 residue amino acid polypeptide. There is no limit that the variance be contiguous. Moreover, there is no requirement that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 90%. Applicants have not described which domain or portions of SEQ ID NOs: 1-2 that are critical to the function(s) of the polypeptide (i.e., reducing analgesic tolerance or one or more symptoms of pain). The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants) are claimed only by their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Regarding the limitation “preventing”, although the specification sets forth a correlation between the CSD polypeptides set forth in SEQ ID NO: 1 and SEQ ID NO: 2 and 4- amino-5-(4-chlorophenyl)-7-dimethylethyl)pyrazolo[3,4-c pyrimidine (PP2), and the function of reducing opioid analgesic tolerance and treating or ameliorating one or more symptoms of pain, the specification does not demonstrate that a CSD polypeptide in combination with a c-Src inhibitor prevents opioid analgesic tolerance or prevents one or more symptoms of pain. It should be noted that the specification also does not define what is encompassed by “symptoms of pain”.
Furthermore, Applicants have not shown a representative number of species that have the claimed function(s). Although the specification sets forth a correlation between the CSD polypeptides set forth in SEQ ID NO: 1 and SEQ ID NO: 2 and 4- amino-5-(4-chlorophenyl)-7-dimethylethyl)pyrazolo[3,4-c pyrimidine (PP2), and the function of reducing opioid analgesic tolerance and treating or ameliorating one or more symptoms of pain, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed CSD polypeptides, and broadly encompass variants sharing 90% sequence identity with SEQ ID NO: 1 and SEQ ID NO: 2. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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 CSD polypeptides and c-Src inhibitors, 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 for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that 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 (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins could not be predicted based on sequence identity to IL-7. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given protein will function in a given manner. Furthermore, as noted by Bowie et al., even conservative substitutions can affect the structure/function relationship of a protein.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of CSD polypeptides. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of recombinant proteins to Applicant. Even if a few structurally identifiable components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize which CSD polypeptide variants and c-Src inhibitor would have the claimed function(s) of reducing opioid analgesic tolerance and treating or ameliorating a symptom of pain. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of CSD polypeptides as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886,1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
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).
Applicant’s Arguments
Applicant argues that the claims expressly recite exemplary species for the genus of c-Src inhibitors. Applicant argues that the specification explicitly correlates these species to the claimed functional effect. Applicant argues that functional data demonstrate that the CSD polypeptides, when combined with c-Src inhibitors such as PP2, reduce or prevent opioid analgesic tolerance. Applicant argues that one of skill in the art could determine the selectivity and suitability of other c-Src inhibitors by routine experimentation without undue burden. Applicant argues that this supports that the genus defined by structurally similar or functionally equivalent compounds is enabled.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. The examiner acknowledges that the claims have been amended to recite specific cSrc inhibitors; However, the claims still encompass a vast genus of CSD polypeptides that are not adequately described. The CSD polypeptide encompasses variants that share 90% sequence identity with the sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 2. As noted in the rejection above, a variance of 10% allows for three amino acids to be changed in the sequence set forth in SEQ ID NO: 1 and two amino acids to be changed in the sequence set forth in SEQ ID NO: 2. This means that the claims encompass millions of possible CSD polypeptides, all of which have the required function of reducing opioid analgesic tolerance. These polypeptides have no correlation between their structure and function. The specification provides no guidance on the structure that must be present for the polypeptides to maintain any given function. Thus, the polypeptide variants encompassed by the claims have no correlation between their structure and function, and the specification does not set forth a representative number of species for such a broad genus of polypeptide variants.
In response to Applicant’s argument that one of skill in the art could screen for could determine the selectivity and suitability of other c-Src inhibitors by routine experimentation without undue burden and the genus defined by structurally similar or functionally equivalent compounds is enabled, at issue is not whether one of skill in the art could envision the detailed chemical structure of the encompassed variant polypeptides, 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 particular method of isolating it. The description of the molecule itself is required. See Fiers V. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes V. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. MPEP 2163 states that "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. In the instant case, the functional characteristics are given without describing the correlation with a particular structure for the variant polypeptides. CSD polypeptides comprising SEQ ID NO: 1 and SEQ ID NO: 2 are supported. It is the requirement for specific functions that are not present within the entire encompassed genus of polypeptides that necessitates the rejection. In other words, not every variant polypeptide that could be included in the genus would necessarily have the required functions. That is because the art teaches making even a single amino acid changes the function of a protein. The specification does not describe the genus in a manner that would allow one of skill in the art to "immediately envisage" the encompassed antibodies or their antigens. Further, the demonstration that two CSD polypeptides have the claimed functions does not adequately describe variant CSD polypeptides sharing 90% sequence identity with SEQ ID NO: 1 and SEQ ID NO: 2. The specification provides no guidance regarding the structure that must be present for the polypeptides to be capable of these required functions. Thus, the variant polypeptides described by the instant specification have no correlation between their structure and their function, and the specification provides insufficient written description to support the genus encompassed by the claims.
New Rejections Necessitated by Applicant’s Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 is indefinite because the claim does not end in a period, and therefore, it cannot be determined if the claim is complete or additional limitations are to be included in the claim. Each claim must begin with a capital letter and end with a period. Dependent claims 12-14 do not remedy the deficiency of claim 11, and thus, are included in the rejection. Appropriate correction is required.
Claim Status
No claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674