DETAILED ACTION
Status of Claims
The new amendment filed 05/12/26 is acknowledged. Claim 1 is presently amended. Claims 10, 11, and 22 are cancelled. Claims 23-25 are new. Claims 1-9, 12-21, and 23-25 are pending and under examination.
Withdrawn Rejections/Objections
The rejection of claims 1 and 10 under 35 U.S.C. 112(b) for being indefinite are withdrawn in view of the amendment to claim 1 removing the indefinite language and the cancellation of claim 10.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-9, 12-21, and 23-25 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 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.
Claim 1 recites a peptide epitope capable of interacting with MHC class II proteins and T cell receptors, the specification, however, fails to adequately describe the species of epitopes that are encompassed by the claim.
There is no evidence in the specification to support that the inventors had possession of the genus contemplated. 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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163. In the instant case, the specification discloses only the sequence AYKAA. The disclosure fails to describe a representative number of species within the genus claimed. Therefore, the specification fails to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed genus. Furthermore, claims 3-9, 12-21 and 23-25 require the copolymer at issue, and are thus also rejected.
Therefore, claims 1, 3-9, 12-21, and 23-25 are rejected under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9, 12-21, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Fridkis-Hareli (2002) in view of Quandt (2004) and in further view of McGraw and Lublin (2013).
Claims 1-9, 12-15, 19, 23, and 24 are drawn to an amino acid copolymer comprised of the amino acids Y, F, A, K, and a peptide epitope. Claims 16-18 are drawn to a product consisting of an amino acid copolymer and a therapeutic agent. Claims 20, 21, and 25 are drawn to a method of treating a disease with a copolymer.
Fridkis-Hareli teachs glatiramer acetate type (henceforth GA-type) random copolymers composed of tyrosine, phenylalanine, alanine, and lysine (YFAK) that bind MHC class II molecules, interact with T-cell receptors [see p. 1636, col. 1, par. 3](instant claim 1). Fridkis-Hareli teaches that these polymers were designed based on the amino acid residues of the immunodominant MBP 85-99 epitope and binding pockets of the MS-associated HLA-DR2 molecule [see abstract], and bind HLA-DR2, inhibit MBP-specific HLA-DR2 restricted T cell responses, and suppress EAE [see p. 1641, col. 1, par. 3-4 and col. 2, par. 1] (instant claim 24). These polymers are generated by solid phase method [see abstract] (claim 12), are polymerized in ratios of 0.2:0.8:5:3 and 0.8:0.2:5:3 (claims 3, 4, 5, 7, and 8), and may be 50 amino acids in length [see p. 1636, col. 1, par. 3] (claim 1). While this Fridkis-Hareli does not teach the specific molar ratios of claims 6 and 9, the claimed ranges represent routine optimization, as optimization of molar ratios were common in the art at the time, as indicated by the various molar ratios disclosed by Fridkis-Hareli [see p. 1636, col. 1, par. 3] (instant claims 6 and 9). Fridkis-Hareli further teaches that when the copolymers are injected into mice via a pharmaceutically acceptable carrier comprising PBS [see p. 1613, col. 1, par. 2] (claim 19), the copolymers inhibit autoantigen-specific T-cell activation and suppress experimental autoimmune encephalomyelitis (the rodent model of Multiple Sclerosis) [see p. 1641, col. 2, par. 3 and 1642, col. 1, par. 1] (claims 21, 24, and 25).
However, Fridkis-Hareli does not teach embedding a peptide epitope sequence within the random copolymer, an acetyl or amide modification, modification to inhibit proteolytic degradation, or the addition of a pharmaceutically acceptable carrier.
Quandt teach the incorporation of MHC class II binding motifs or peptide epitopes associated with MS and EAE into random peptide mixtures that are used as immunotherapeutic agents [see abstract] (claims 1 and 23). These random peptide mixtures are conceptually similar to the claimed random peptide in that both comprise heterogeneous peptide compositions that modulate immune responses via MHC class II interactions and are similar in nature to glatiramer acetate. Quandt teaches that these short peptides in the 10-20aa range, particularly those in the 10-12aa range, can be highly stimulatory and generate large numbers of T cells in cell cultures of PBMCs derived from MS patients and healthy individuals [see p. 1079, col. 2, par. 1; see p. 1081, col. 2, par. 1] (claims 1 and 24). Quandt further teaches the inclusion of an acetyl group in the peptide [see p. 1079, col. 1, par. 2], but although Quandt does not specifically state that it is modified at the N-terminal, such modifications were routine in the art at the time to improve stability, and a person of ordinary skill in the art would have understood such a modification to have occurred at the N-terminal (claim 13). Similarly, Quandt does not teach modification of the C-terminal amino acid with an amide group, however, such modifications were routine in the art to improve stability and resistance to proteolytic degradation (claims 14 and 15).
The combination of Fridkis-Hareli and Quandt does not teach or suggest an additional therapeutic.
McGraw and Lublin disclose a combination therapy for the treatment of Multiple Sclerosis that comprises administration of the cytokine Interferon Beta and glatiramer acetate.
It would have been obvious to one of ordinary skill in the art to combine these teachings and introduce defined peptide epitopes capable of binding MHC class II proteins and T cell receptors into GA-type copolymers like YFAK given the known effects of composition changes on immunomodulatory activity and to leverage the nonspecific antigenic properties of the random copolymer together with the enhanced recognition of the selected epitope. There would be a reasonable expectation of success given that the mechanisms of action for both the random peptide and peptide epitope were known and MHC peptide binding motifs were known to retain their function in random peptide mixtures. It would have been obvious to select an embedded epitope between about 5 and 20 amino acids because Quant teaches that short peptide sequences in the 10-20 amino acid range can be designed based on MHC anchor residues, and such epitopes possess enhanced immunomodulatory activity (claim 1). Similarly, given that Fridkis-Hareli teaches of 50 amino acids, it would have been obvious that a copolymer generated with the combined disclosures would be between 30 and 200 amino acids. Finally, the precise selection of a particular peptide epitope, such as AYKAA, would have constituted routine optimization based on known MHC class II binding characteristics (claim 2).
Regarding claims 16-18, because the claimed copolymer is a GA-type copolymer and used for the same immune mediated disorders and acting through the same mechanisms, it would have been obvious to combine the claimed copolymer with a cytokine such as Interferon Beta as disclosed by McGraw and Lublin. There would be a reasonable expectation of success as because such therapies were known in the art to be successful.
It would have been obvious to combine these teachings and generate a copolymer with a peptide epitope that is associated with an immune-mediated disorder autoimmune disease, and reasonably expect the copolymer to bind an MHC molecule associated with such disease, because both Fridkis-Hareli and Quandt teach that modifying the amino acid composition and selecting a peptide epitope that is associated with MS can enhance epitope/MHC binding and increased T-cell responses (instant claims 23 and 24).
Similarly, the combination of reference each separately and in combination teach GA-type immunomodulatory copolymers for treating autoimmune and immune mediated diseases, with particular identification of Multiple Sclerosis. It would have been obvious to combine these teachings and utilize the claimed copolymer for the treatment of MS as the art teaches therapeutic efficacy in this population (instant claims 20, 21, and 25).
Therefore, claims 1-9, 12-21, and 23-25 are rejected under 35 U.S.C. 103.
Response to Arguments
35 USC § 112(a)
Applicant argues that the written description is adequately satisfied because the specification describes the claimed copolymer using both structural and functional language. Applicant points to the disclosure of a random polypeptide comprising amino acids such as Y, F, A, K, an embedded peptide epitope for fixed length, and the ability of the EERP to bind MHC class 2 proteins in at least one pocket of the binding groove. Applicant further relies on the specification’s teaching that structurally or charge related amino acids may be substituted, and identifies several embodiments comprising various possible combinations of amino acids. Applicant argues that, in light of the specification, a person having ordinary skill in the art would understand that an EERP comprising the peptide epitope AYKAAA is illustrative of the claimed genus and that the written description requirement does not require examples of every possible embodiment.
Applicant's arguments have been fully considered but they are not persuasive. Applicant’s reliance on the numerous EERP embodiments containing different combinations of amino acids does not cure the deficiency because those disclosures demonstrate variation in the random copolymer portion of the EERP rather than possession of the broad genus of embedded peptide epitopes to which the rejection was directed. Similarly, the general disclosure that EERPs can bind at least one pocket of MHC class 2 proteins does not adequately indicate possession of the claimed epitope genus. MHC class II molecules are highly polymorphic, and polymorphic differences among MHC class II molecules alter the structure and chemical composition of the peptide binding groove, including the pocket size, shape, charge, and other characteristics [see Jones, abstract]. Thus, different molecules can exhibit different binding selectivity and specificity. As such, although a person having ordinary skill in the art would have understood that an embedded peptide must interact with one or more binding pockets, that general understanding would not have identified a particular peptide sequence in the claimed genus. The specification only demonstrates AYKAAA as an embedded epitope, but does not establish a correlation between the disclosed sequence and the broad genus of 5-20 residue sequences capable of both MHC class 2 binding and TCR interaction. As such, even though the specification provides an operative example and describes the general concept of an embedded epitope, it does not convey that the inventors were in possession of the full genus of peptide epitopes encompassed by independent claim 1.
Accordingly, the rejection of claims 1, 3-9, 12-21, and 23-25 under 35 U.S.C. 112(a) is maintained.
35 USC § 103
Applicant argues that the combination of references does not teach or suggest the claimed limitations of a copolymer comprising 30-200 amino acids and an embedded epitope comprising 5-20 amino acids as required by presently amended claim 1. Applicant argues that Fridkis-Hareli discloses YFAK/FAK copolymers, but not an embedded epitope; Quandt discloses shorter, defined peptide mixtures, but not YFAK (only omitting cysteine) or an embedded epitope in a 30-200 amino acid random YFAK polymer; and McGraw merely discusses GA/Copaxone and IFN-B. Applicant argues there would have been no motivation to combine the references because Fridkis-Hareli teaches away from GA type compositions as disclosed by Quandt by showing that YFAK is more effective than GA/Copaxone. Applicant further argues that the combined references provide no predictable results. Applicant notes that the specification’s AYKAAA data demonstrates unexpected superiority that could not have been predicted. Applicant extends the same argument to the dependent claims and newly added autoimmune disease treatment claims.
Applicant’s arguments have been fully considered but they are not persuasive. Fridkis-Hareli teaches random amino acid copolymers, including 50-mer YFAK and FAK polymers, designed based on the amino acid residues and MHC binding pockets of immunodominant epitopes. Fridkis-Hareli further teaches that these random copolymers exhibit improved MHC binding, inhibition of antigen specific T-cell responses, and suppression of EAE compared with Copolymer 1 (Cop 1). Thus, Fridkis-Hareli provides the claimed random YFAK peptide framework and establishes that selection of amino acids based on known MHC/epitope binding characteristics was an established strategy for optimizing immunomodulatory copolymers.
Quandt is not relied upon to teach YFAK, as Fridkis-Hareli does so above, but instead Quandt separately teaches the general importance of specific peptide epitopes, MHC binding motifs, anchor residues, peptide length, and MHC bias in designing immunomodulatory peptide compositions. Quandt teaches that PSCL analysis has been used to identify an “ideal antigen” recognized by GA-specific T-cell clones, while also teaching that increasing sequence complexity can enhance stimulation [see p. 1081, col. 1, par. 3]. Quandt discloses designing molecules based on residues of immunodominant T-cell epitopes interacting with disease-associated MHC molecules. Quandt further states that synthetic copolymers tailored according to binding motifs of immunodominant epitopes and MHC binding pockets could provide improved therapeutic potential [see p. 1084, col. 2, par. 2]. Accordingly, one would have had reason to employ the known MHC binding epitope information of Quandt when modifying or further optimizing the random copolymers of Fridkis-Hareli as Quant teaches the benefits of “ideal antigens,” additional sequence complexity, and shorter peptide epitopes.
Applicant’s argument that Quandt’s peptides are only 10-20 amino acids is not persuasive because the claimed 30-200 amino acid limitation is satisfied by the 35- and 50-mer random copolymers expressly disclosed by Fridkis-Hareli, while the 5-20 amino acid epitope limitation is taught by Quandt. Combining these teachings would have involved using known elements, each known in the art to be beneficial, for their established purposes. The fact that Quandt’s complex mixtures were shorter than the random copolymers of Fridkis-Hareli does not diminish their teachings in regards to MHC-binding epitopes and anchor residues, or the obviousness of the teachings being applied to longer random copolymers. Similarly, McGraw is not relied upon to teach the claimed complex mixtures or embedded peptide epitope, but instead to establishes that similar such compounds were known in the art to be co-administered with additional therapeutic agents.
Applicant’s argument that Fridkis-Hareli teaches away is not persuasive because, although it reports that YFAK and FAK can outperform COP 1 in certain assays, the reference does not criticize, discredit, or otherwise discount further use and modification of the random copolymers. Conversely, Fridkis-Hareli expressly states that development of novel copolymers based on accumulated knowledge could result in improved therapeutic materials [see p. 1640, col. 2, par. 1]. With this Fridkis-Hareli provides an affirmative motivation to continue to optimize random copolymers based on known MHC/epitope interactions.
Applicant’s argument that the claimed combination lacks a reasonable expectation of success is not persuasive because both Fridkis-Hareli and Quandt recognize that the activity of random copolymers is associated with their interaction with MHC class II molecules and T-cell responses. Quandt specifically teaches that amino acid composition, peptide length, and MHC anchor residues can be manipulated to alter biological activity, while Fridkis-Hareli demonstrates that modifying the amino acid composition of random copolymers can improve MHC binding and therapeutic activity. Accordingly, one would have reasonably expected that incorporating a known MHC binding epitope or motif into an immunomodulatory random copolymer would produce an active immunomodulatory composition, even if the precise degree of improvement was not predictable because the art teaches that both of these factors independently improve peptide efficacy.
Applicant’s argument of unexpected results is not persuasive because evidence of superior properties in one species insufficient to establish the nonobviousness of a subgenus containing hundreds of compounds [see MPEP 2145]. Unexpected results must be commensurate in scope with the claims and must establish that the unexpected property is attributable to the claimed distinguishing feature. Here, the data relied upon concern the particular AYKAAA epitope embedded in a particular copolymer, whereas claim 1 broadly encompasses any peptide epitope of 5-20 amino acids embedded in a 30-200 residue random YFAK polypeptide. Applicant has not demonstrated that the claimed superiority is present across the full scope of the claimed genus.
Conclusion
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 Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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/TIRONE D. JOHNSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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