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 .
Priority
The present Application, filed November 3, 2022, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/EP2021/061972, filed May 6, 2021, which claims priority to European Patent Application No. EP20179019, filed June 9, 2020 and to European Patent Application No. EP0173209, filed May 6, 2020.
Status of the Claims
In the amendment filed April 28, 2023, claims 20-22 and 24-25 are canceled and new claims 3-19 and 23 are amended. Claims 1-19 and 23 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 3, 2022 is acknowledged.
Specification
The specification is objected to for misspelling “juvenile diabetes” as “juveline diabetes” at pg. 7, line 5; pg. 22, line 2; and pg. 61, line 3. Appropriate correction is required.
Claim Objections
Claim 1 is objected to for ending with two periods.
Claim 9 is objected to for reciting, “wherein the T cell epitope is an NKT cell epitope has the amino acid motif,” in line 2. This is awkward syntax, and appears to be missing a word (e.g. “wherein the T cell epitope is an NKT cell epitope that has the amino acid motif….” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-19, and 23 are indefinite:
Claims 1-5, 7-19, and 23 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 1 is indefinite for reciting, “an antigenic protein involved in a fumarate-related disease or disorder,” because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. As a first matter, one of ordinary skill in the art could not clearly know what it means for a protein to be “involved in” a given disease. This could require, for example, that the protein’s activity be understood as contributing to disease onset or progression; it could refer to all proteins in which aberrant activity, structure, or expression, etc. is typically observed as symptomatic of the disease, but not necessarily causal; it could refer to any protein that has been suggested in the art as being potentially therapeutically relevant; or it could refer to some combination of these things or other potential descriptions. In short, the phrase “involved in” in this context is vague, and its meaning is uncertain.
Furthermore, it would be uncertain what are the metes and bounds of the phrase “a fumarate-related disease or disorder.” The instant specification lists several exemplary categories of diseases in paragraph [0034] and a larger number of exemplary specific diseases or disorders in paragraph [0035], but neither of these lists is explicitly presented as being exhaustive. As such, it can be presumed that some unnamed diseases are intended to be encompassed, but it would be unclear whether is limited to diseases in which fumarate dysregulation (e.g. excessive fumarate accumulation) is observed as a common symptom, whether it is limited to diseases, such as autoimmune diseases and some cancers, in which the immunomodulatory properties of fumarate are thought to be potentially therapeutically beneficial, or some other criteria. Claims 2-5, 7-19, and 23 are indefinite for depending from claim 1 without curing these points of indefiniteness.
Claim 6, depending from claim 1, recites the limitation "said autoantigen" in lines 2, 8, and 11. There is insufficient antecedent basis for this limitation in the claim. It is thought that this term is perhaps intended to refer to the antigenic protein of claim 1.
Claim 9 is further indefinite for reciting, “wherein the T cell epitope is an NKT cell epitope has the amino acid motif [FWHY]XX-[ILMV]-XX-[FWHY] (SEQ ID NO: 51 ), preferably the amino acid motif [FW]-XX[ILMV]-XX-[FW] (SEQ ID NO: 52),” because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. Ordinarily, the formulation of “wherein a feature is X, preferably Y,” X is required, and Y is a preferred subspecies of X. In the present case, however, the sequences listed appear to be alternative, not a required broader version and a preferred narrower version, because a sequence can conform to SEQ ID NO: 52 but not to SEQ ID NO: 51. This renders the meaning of the phrase unclear. For the purpose of compact prosecution, claim 9 will be examined against the prior art according to an interpretation wherein SEQ ID NO: 51 and SEQ ID NO: 52 are alternatives (wherein the epitope has SEQ. ID NO: 51 or 52, but preferably 52).
Claims 16 and 17 are further indefinite for reciting that the peptide comprises “a flanker,” but do not indicate where the flanker is positioned in the peptide. On the basis of the specification, it is presumed that the “flanker” may be located at the N-terminus of the peptide (see pg. 92, lines 4-8 describing SEQ ID NO: 176, having a “flanking sequence” at the N-terminus), but this should be clarified in the claim, or deleted.
Claim 19 recites the “said immunogenic or tolerogenic peptides” in lines 2 and 3. This plural formulation lacks proper antecedent basis because claim 1, from which claim 19 depends, recites the singular, “an immunogenic or tolerogenic peptide.” This mismatch between the singular formulation of the base claim and the plural formulation of the dependent claim creates a failure of proper antecedent basis.
Claim Rejections - 35 USC § 112(a)
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 1-5, 7-19, and 23 fail to comply with the written description requirement:
Claims 1-5, 7-19, and 23 are rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. The claims 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 inventors, at the time the application was filed, had possession of the claimed invention.
Specifically, Applicant does not have written description support for a kit having a fumarate compound and an immunogenic or tolerogenic peptide comprising a T cell epitope of an antigenic protein involved in any fumarate-related disease or disorder. Similarly, Applicant does not have written description support for a method of treating any fumarate-related disease or disorder. As discussed further below, the examples of the instant specification only involve, and demonstrate only treatment of an animal model for multiple sclerosis (MS). Furthermore, the art indicates that at least some fumarate -related disease or disorders, especially some cancers, would be unlikely to be beneficially treated by the claimed combination of therapeutics. As such, the present claims other than claim 6 lack sufficient written description.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 3 79 F .2d 990, 154 USPQ 118 (CCP A 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicants claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
A component of Applicant’s invention is directed kits having two therapeutic components for the treatment of “fumarate-related diseases and disorders.” The first component is a fumarate compound – methyl or dimethyl fumarate – and the second component is an immunogenic or tolerogenic peptide. The peptide includes a T cell epitope of an antigenic protein involved the fumarate-related disease, so that the peptide will induce an immune response comparable to that induced by the native antigen. In the case of an autoimmune disease like MS, this could be an epitope from myelin oligodendrocyte glycoprotein, which is pathologically antigenic in the disease state. In some instances, this induction of an immune response may be ultimately tolerogenic such that, in the example of MS, the pathological immune response to the native antigen may be diminished. The peptide can optionally include an oxidoreductase motif which may increase this tolerogenic effect in some cases, and the fumarate compound may likewise increase this tolerogenic effect in some cases.
The Claimed Invention
The claimed invention is directed to a pharmaceutical kit having (i) a fumarate compound (methyl or dimethyl fumarate) and (ii) an immunogenic or tolerogenic peptide comprising a T cell epitope of an antigenic protein involved in a fumarate-related disease or disorder. Many dependent claims (2 and 7-19) specify details regarding the peptide. Of significance, claim 2 specifies an optional oxidoreductase motif that can be adjacent to the epitope and can be separated from the epitope by a short linker. Claims 16-17 reference a short flanker sequence without specifying its location, it appears that it may be typically at the N-terminus of the peptide. In embodiments having all four sequence components, a typical arrangement from C- to N-terminus would be redox motif-linker-epitope-flanker.
Claims 16-18 specify sequences of different portions of the peptide, with claim 18 reciting seven alternative full-peptide-length sequences. Claims 3-4 specify details about the fumarate component of the kit, while claims 5-6 specify details about the fumarate-related disease that the antigen is involved with an implication that this is the disease to be treated by the kit. Claim 23 recites a method of treating the disease involving administering the kit (i.e. the two components) to a subject in need.
The Supporting Disclosure
Applicants' supporting disclosure, after providing background (pgs. 1-3), summarizes various aspects of the invention, substantially mirroring the claim language (pgs. 3-24). At pgs. 26-78, the disclosure provides detailed descriptions of various terms, and then the Examples, beginning at pg. 78, are of particular relevance to the present rejections. Four Examples are provided (Examples 1-4), each of which tests one or more peptides having a MOG-derived epitope, that is directed to treatment of MS.
Example 1 evaluates a peptide having a MOG-derived epitope, along with a redox fragment, linker, and flanker. This peptide is thus directed to treatment of MS. Correspondingly, all testing is done in mice induced with experimental auto-immune encephalomyelitis (EAE), an animal model for MS. The peptide is tested alone and in combination with dimethyl fumarate (DMF), the results showing at least an additive effect. The disclosure states that there is a “tendency toward synergy” based on p-value of 0.2373.
Examples 2-4 likewise exclusively test peptides having MOG-derived epitopes and therefore being exclusively directed toward MS. Correspondingly, Examples 2-4 exclusively test these variations in EAE induced mice. To reiterate, all working examples of the disclosure deal with peptides, and thus variations of the kit and method, that are expressly directed exclusively to MS as the fumarate-associate disease or disorder.
The State of the Art
It is known in the art that tolerogenicity is desirable in treating an auto-immune disease – so that the pathological autoimmunity will be diminished. See, for example, the non-patent publication, Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, Tregs, and Tolerogenic Dendritic Cells, Frontiers in Immunology, 12, article 657768 (2021) by Moorman et al. It is conversely but equally known that immunogenicity, the opposite of tolerogenicity, is desirable in treating cancer, so that the immune system will aggressively attack cells presenting an antigenic oncogene. See, for example, the non-patent publication, Immunological aspects of cancer chemotherapy, Nat. Rev. Immunol., 8, pgs. 59-73 (2008) by Zitvogel et al. Further to this point, tolerogenicity in the case of cancer is generally counterproductive. See, for example, the non-patent publication, Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion, Science, 331, pgs. 1565-1570 (2011) by Schreiber et al.
A number of references establish, however, indicate that the effect of fumarate compounds on tolerogenicity vs immunogenicity is complicated, but that in at least some cancers, fumarate has an immunosuppressive effect. For example, the non-patent publication, Fumarate suppresses B-cell activation and function through direct inactivation of LYN, Nat. Chem. Biol., 18, pgs. 954-962 (2022) by Cheng et al. teaches that:
Fumarate accumulation by FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation, proliferation and antibody production.
-Abstract
Similarly, the non-patent publication, Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment, Cell Metab., 35, pgs. 961-978 (2023) by Cheng et al. teaches
tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
-Abstract
These teachings demonstrate that, in at least some cancer environments, fumarate accumulation is likely to have a detrimental effect on disease treatment and is likely to contribute to disease progression.
Summary of Written Description Rejection
In view of the findings described above, it is likely that administration of a fumarate compound such as DMF would have adverse effects on treatment of some cancers. As such, even if it is assumed that the immunogenicity/tolerogenicity of the claimed peptides can be appropriately tailored, or at least predicted, for treatment of different diseases that require tolerogenicity or immunogenicity, it cannot be reasonably assumed that combination of DMF with such peptides would be beneficial. In some instances, it would likely be detrimental.
Given this, and in view of the lack of working examples testing disclosed combinations for treatment of cancer, or any disease other than MS, the claim to kits for treatment of all “fumarate-related diseases and disorders” is overly broad. At minimum, there is insufficient support for kits and methods treating cancers as a whole. For this reason, claims 1-5, 7-19, and 23 fail to comply with the written description requirement.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. § 112(b):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected for failing to include all limitations of the base claim from which it depends:
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1, from which claim 19 depends, recites a kit that includes an immunogenic or tolerogenic peptide. Claim 19 recites that the peptide is “in the form of” one or more nucleic acid molecules. However, claim 1 requires that a peptide be present in the kit, and a nucleic acid molecule is not a peptide, even if the nucleic acid sequence encodes the peptide sequence. As such, a kit of claim 19 is outside the scope of claim 1, as the claims are currently recited. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8, 10-15, 19, and 23 are obvious over Fox, Saint-Remy, and Clozel:
Claims 1-8, 10-15, 19, and 23 are rejected under 35 U.S.C. § 103 as being unpatentable over the non-patent publication, BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety, Curr. Med. Res. & Opin., 30, pgs. 251-262 (2014) by Fox et al. (hereinafter, “Fox”), in view of U.S. Patent Application Publication No. 2018/0228912 to Saint-Remy et al. (hereinafter, “Saint-Remy”), in view of International Patent Application Publication No. WO2016/092042 by Clozel et al. (hereinafter, “Clozel”).
Claim 1 recites a pharmaceutical kit comprising:
a) one or more dosage forms of a fumarate compound selected from the group consisting of: dimethyl fumarate (DMF), monomethyl fumarate (MMF), compounds that can be metabolized into MMF in vivo, and combinations thereof; and
b) one or more dosage forms of an immunogenic or tolerogenic peptide comprising a T cell epitope of an antigenic protein involved in a fumarate-related disease or disorder.
Fox teaches dimethyl fumarate (DMF) is approved for the treatment of relapsing forms of multiple sclerosis (MS) – pg. 2, left column, first full paragraph; teaching that DMF had demonstrated beneficial effects in preclinical models of neuro-inflammation, neurodegeneration, and toxic oxidative stress, but that its precise mechanism of action was unclear (pg. 2, right column, first full paragraph). Fox further teaches that the anti-inflammatory and immunomodulatory effects of dimethyl fumarate would be predicted to have a beneficial impact on pathological processes in patients with MS. Fox thus teaches that beneficial therapeutic effects are to be obtained by administration of dimethyl fumarate to a subject having MS, but does not expressly teach the benefits of administering an immunogenic or tolerogenic peptide as described in instant claim 1. It would have been obvious to combine such a peptide for administration with the dimethyl fumarate of Fox, however, because such peptides were known in the art to likewise be therapeutically beneficial in the treatment of MS. See, for example, Saint-Remy.
Saint-Remy teaches immunogenic peptides of between 13 and 100 amino acids comprising a MHC class II T cell epitope of an antigen and an adjacent redox motif sequence, for use as a medicament (claim 1). Saint-Remy teaches that the peptides can be used in the prevention or treatment of MS, whereby the antigen is an auto-antigen involved in MS (paragraph [0017]), and that the peptide can be formulated for any of a variety of routes of administration (paragraph [0197]). Saint-Remy thus teaches one or more dosage forms of an immunogenic or tolerogenic peptide comprising a T cell epitope of an antigenic protein involved in a MS (a fumarate-related disease or disorder). One would thus have had a reasonable expectation of success in obtaining at least an additive combination effect by combining the dimethyl fumarate of Fox with an immunogenic peptide of Saint-Remy.
While the combination would have been obvious over Fox and Saint-Remy, neither Fox nor Saint-Remy expressly teaches incorporating the therapeutic entities (DMF and/or immunogenic peptide) in a kit. Incorporation of the components into a pharmaceutical kit would have been obvious, however, because kits for combination therapy of MS were well-known in the art. See, for example, Clozel.
Clozel teaches a pharmaceutical composition having ponesimod as a first active ingredient and DMF as a second active ingredient (pg. 1, lines 19-26), and taches the combination is effective for the treatment of MS (pg. 2, lines 15-17 and lines 21-23). Clozel further teaches incorporating these components into a kit, having the first and second active ingredients for the treatment of MS (pg. 7, lines 15-24). Clozel teaches such a kit can have instructions, e.g. for different orders of taking the two components (pg. 7, lines 28-30). It thus would have been obvious to incorporate the first and second active ingredients of the method of Fox and Saint-Remy into a kit of the type of Clozel, effectively merely replacing the ponesimod of Clozel with the immunogenic peptide of Saint-Remy, for example to include instructions or otherwise improve the convenience or ease of administering the combination therapy of Fox and Saint-Remy. Claim 1 is thus obvious over Fox, Saint-Remy, and Clozel.
With respect to claim 2, Saint-Remy teaches that the T cell epitope is separated by at most 7 amino acids (linker of 0 to 7 a.a.) from the redox motif (oxidoreductase motif), which can be one of several motifs overlapping with the general oxidoreductase motif formulae of claim 2, such as H-C-X(2)-[CST] [SEQ ID NO:78 of Saint-Remy] (Saint-Remy claim 1). Saint-Remy thus teaches the features of instant claim 2. With respect to claims 3 and 4, as noted, Fox teaches the fumarate is dimethyl fumarate.
With respect to claim 5, the MS of Fox, Saint-Remy, and Clozel is both an auto-immune disorder and a demyelinating disorder (see the instant specification at pg. 61, lines 23 and 31-32). With respect to claim 6, the disease or disorder of the kit of Fox, Saint-Remy, and Clozel is MS, as noted. Furthermore, Saint-Remy teaches that the autoantigen for MS can be MOG, MBP, or PLP (paragraph [0144]).
With respect to claim 7, the MOG of Saint-Remy does not naturally comprise an oxidoreductase motif within 11 amino acids of the epitope and the epitope of MOG (e.g. VVHLYRNGK [SEQ ID NO:3 of Saint-Remy] – claim 19 of Saint-Remy) does not naturally comprise an oxidoreductase motif in its sequence. With respect to claim 8, as noted, Saint-Remy teaches wherein the T-cell epitope is an MHC class II T-cell epitope (Saint-Remy claim 1).
With respect to claim 10, Saint-Remy teaches wherein the motif is located N-terminally from the epitope (examples in paragraph [0234]). With respect to claim 11, Saint-Remy teaches examples wherein the epitope has a length of between 7 and 20 amino acids, with a particular example having 9 amino acids ([SEQ ID NO:3 of Saint-Remy] – claim 19 of Saint-Remy, sequence shown above). With respect to claim 12, Saint-Remy teaches that in different embodiments, the peptide can have a length between 13 and 50 amino acids or between 13 and 30 amino acids (Saint-Remy claims 9 and 10). While this is not identical to the 9-50 or 9-30 ranges of instant claim 12, it broadly overlaps.
With respect to instant claim 13, the redox motifs of Saint-Remy claim 1 (e.g. H-X(0,2)-C-X(2)-[CST]) broadly overlap with the oxidoreductase motifs of instant claim 13 (e.g. Zm-C-Xn-[CST]-). With respect to claim 14, Saint-Remy teaches wherein the immunogenic peptide has a redox (oxidoreductase) motif which comprises (along with the N-terminus) the sequence HCPYC (instant SEQ ID NO: 71), see Saint-Remy paragraph [0234], Seq id 108, for example. With respect to claim 15, as noted, Saint-Remy teaches wherein the immunogenic peptide comprises a T-cell epitope derived from MOG (paragraph [0144]). The preferred sequences of claim 15 are, as mere preferences, not required.
With respect to claim 19, Saint-Remy teaches that the invention also relates to nucleic acid sequences encoding the disclosed immunogenic peptides (col. 24, lines 20-24). It thus would have been obvious to incorporate an immunogenic peptide-encoding nucleic acid into the kit of Saint-Remy, Fox, and Clozel.
Claim 23 recites, inter alia, a method of treatment of a fumarate-related disease in a patient in need thereof, comprising the step of administering an effective amount of the pharmaceutical kit (i.e. of the component combination contained in the kit) according to claim 1. Clozel teaches a method for the treatment of a listed disease (e.g. MS) comprising administering to a subject in need thereof a pharmaceutically active amount of a disclosed pharmaceutical combination. It thus would have been obvious to apply the method of Clozel to the kit of Fox, Saint-Remy, and Clozel, by administering the components of the kit to a subject in need for the treatment of MS.
Claim 9 is obvious over Fox, Saint-Remy, Crozel, and Saint-Remy2:
Claim 9 is rejected under 35 U.S.C. § 103 as being unpatentable over Fox, in view of U.S. Saint-Remy, in view of Clozel, and further in view of U.S. Patent No. 10,023,847 to Saint-Remy (Saint-Remy2).
Claim 9 recites the kit of claim 1, wherein the T cell epitope is an NKT cell epitope has the amino acid motif [FWHY]XX-[ILMV]-XX-[FWHY] (SEQ ID NO: 51 ), preferably the amino acid motif [FW]-XX[ILMV]-XX-[FW] (SEQ ID NO: 52).
Saint-Remy, Fox, and Clozel are applied to claim 9 as to claim 1, above, but none expressly teaches the peptide having one of the T cell epitopes of claim 9. It would have been obvious to utilize such an NKT cell epitope, because the use of such epitopes in analogous immunogenic peptides was known in the art. See, for example, Saint-Remy2.
Saint-Remy2 teaches immunogenic peptides useful for treating autoimmune diseases (col 1. lines 22-24). Saint-Remy2 teaches that the peptides have an NKT cell epitope and a thiol-oxidoreductase motif (col. 6, lines 24-34), analogous to the MHC class II T-cell epitope and redox motif of Saint-Remy. Saint-Remy2 teaches that the epitope can be derived from an autoantigen (col. 6, lines 16-20), and that the autoantigen can be associated with multiple sclerosis and, in particular, can be derived from MOG (col. 16, lines 4-24). Saint-Remy2 teaches that in particular embodiments, the epitope can conform to instant SEQ ID NO: 51 (col 14, lines 50-54).
Claims 16 and 18 are obvious over Fox, Saint-Remy, Crozel, and Saint-Remy2:
Claim 9 is rejected under 35 U.S.C. § 103 as being unpatentable over Fox, in view of U.S. Saint-Remy, in view of Clozel, and further in view of the non-patent publication, GenBank: EDL23322.1, disclosing the sequence of mus musculus MOG, obtained at the url www.ncbi.nlm.nih.gov/protein/EDL23322.1 (2016) (hereinafter, “EDL23322.1”). It will be noted that EDL23322.1 is based on the article, A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome, Science, 296, pgs. 1661-1671 (2002) by Mural et al.
Claim 18 recites the kit of claim 1 wherein the peptide is one of seven specifically enumerated peptides, such as HCPYCGWYRSPFSRVVHLYR (SEQ ID NO: 185). Notably, this sequence contains a redox sequence HCPYC, a linker sequence GW; a MOG-derived epitope, YRSPFSRVV; and a flanker sequence, HLYR. Thus, this particular peptide of claim 18 includes a linker-epitope-flanker combination of claim 16, plus the N-terminal redox sequence, HCPYC.
Fox, Saint-Remy, and Crozel are applied to claims 16 and 18 as to claim 1, above. Saint-Remy further teaches a MOG peptide fragment YRPPFSRVVHLYRNGKD (SEQ ID NO:4, paragraph [0216] having one of the epitope sequences of instant claim 16 (nearly identical to the epitope YRSPFSRVV of claim 18) and the flanker sequence, but does not expressly disclose the linker. Saint-Remy further teaches the redox fragment HCPYC (Saint-Remy SEQ ID NO:6) that it uses to replace a portion of the MOG fragment for production of a disclosed peptide (paragraphs ([0211] and [0216]). As noted, however, Saint-Remy does not disclose the linker of claim 16 or 18, or disclose a precise sequence combination of claim 18. However, Saint-Remy discloses that the exemplary immunogenic peptide SEQ ID NO:1 is produced by merely taking a 17 a.a. fragment of human MOG and replacing the N-terminal five amino acids with the redox HCPYC motif (paragraph [0216]). Saint-Remy also teaches that the fragment can be derived from any mammal (paragraph [0045]). In combination with the teachings of EDL23322.1.
EDL23322.1 teaches the sequence of murine MOG, having amino acids 1-200. EDL23322.1 teaches that the fragment 63-81 has a sequence GMEVGWYRSPFSRVVHLYR, and includes the epitope fragment used in Saint-Remy paragraph [0216]. Replacement of the five N-terminal amino acids of this fragment with the redox HCPYC motif of Saint-Remy produces the immunogenic peptide SEQ ID NO: 185 of instant claim 18. This peptide is also a peptide of instant claim 16, having an epitope, linker, and flanker as defined in claim 16. It would have been obvious to select a variety of fragments around this epitopic region of mammalian MOG to replace the N-terminal region with the redox fragment of Saint-Remy, to produce immunogenic peptides of Saint-Remy.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. 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.
/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629