DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The preliminary amendment of 4/27/23 has been entered in full. The specification is amended. Claims 3, 5-6, 12, 16, 19, 21 and 24-26 are amended. Claims 10-11, 14-15, 18 and 23 are canceled. Claims 1-9, 12-13, 16-17, 19-22 and 24-26 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because in part it refers to “use thereof”, but the claims are directed to methods of treatment. A new title is required that is clearly indicative of the invention to which the claims are directed. In view of the claim rejections set forth below, the following title is suggested: “BCMA-TARGETING SINGLE DOMAIN ANTIBODY AND METHOD OF USING SUCH TO TREAT PLASMA CELL MALIGNANCY”.
---The disclosure is objected to because it contains an embedded hyperlink (browser-executable code) at ¶ 164. Applicant is required to remove the embedded hyperlink; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01 (VII).
Appropriate correction is required.
Claim Objections
Claims 1-9, 12-13, 16-17, 19-22 and 24-26 are objected to because of the following informalities:
In claim 1, the acronym BCMA should be accompanied the full terminology the first time it appears in a series of claims; e.g., “BCMA (B cell maturation antigen)”. See the specification at ¶ 2.
In claim 13, line 2, “(Fab’)2” should be “(Fab’)2”.
The remaining claim(s) are objected to for depending from an objected claim.
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 3-4, 7-8, 22 and 26 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 pre-AIA the applicant regards as the invention.
In claim 3, line 9, the recitation of “the variant” (singular) has unclear antecedent basis because the claim refers to “variants” (plural) in multiple places; specifically, line 4, 6, 7 and 9. Thus, the antecedent basis is unclear because of the different between “the variant” and “variants”, and also because multiple groups of variants are referred to. Because of this difference, it is unclear whether one or all of the “variants” are further limited by “the variant”.
Claim 4 is indefinite for the same reason as claim 3, with respect to each of parts (1)-(5), each of which refers to “variants” and “the variant”.
Claim 7 is indefinite for the same reason as claim 3, referring to “the variant” on line 11 and “variants” on lines 4, 6, 8 and 11.
Claim 8 is indefinite for the same reason as claim 3, with respect to each of parts (1)-(4), each of which refers to “variants” and “the variant”.
In claim 22, lines 22-23, the recitation of “recombinant polyethylene glycol molecule” is indefinite because polyethylene glycol (PEG) is a non-protein polymer, and not a protein, and thus it is unclear how PEG can be “recombinant”, which generally refers to proteins that are expressed in a host cell.
Claim 26 recites the limitation “the disease associated with BCMA expression” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 26 depends from claim 25, which recites “a disease related to BCMA expression”, which differs in wording from what is recited the dependent claim, and does not provide clear antecedent basis for the recitation in the dependent claim.
Claim Rejections - 35 USC § 112, enablement
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 25 and 26 are 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:
A method for treating and/or preventing and/or diagnosing a plasma cell malignancy related to BCMA expression, comprising administering to a subject the single domain antibody according to claim 1,
does not reasonably provide enablement for:
A method for treating and/or preventing and/or diagnosing a disease related to BCMA expression, comprising administering to a subject the single domain antibody according to claim 1.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claimed invention of claims 25 and 26 is a method with the intended goal of treating, preventing and/or diagnosing a disease related to the receptor protein BCMA (B-cell Maturation Antigen), which the specification teaches is “a member of the tumor necrosis receptor (TNFR) superfamily” that is “mainly expressed in plasma cells and mature B cells” and can “specifically bind to B cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL)” (¶ 2). The relevant art published in the same year prior to the earliest effective filing date of the instant application (10/30/20) further explains that BCMA “plays a critical role in regulating B-cell proliferation and survival, as well as differentiation into plasma cells” (page 1 of Dogan et al, 2020 Jun 30, Blood Cancer Journal. 10: 73; pages 1-13 as printed). The goals of claimed method are asserted to be achieved via a single step of administering a “single domain antibody” (sdAb) of claim 1, which is an anti-BCMA sdAb comprising three CDRs defined by amino acid sequence, such as SEQ ID NO: 1-3.
The specification teaches that diseases associated with BCMA broadly include “cancer, autoimmune diseases, infectious diseases” (¶ 2). The specification further enumerates various embodiments of autoimmune diseases that are encompassed by the claims, including approximately 28 different types of autoimmune disease of differing etiologies:
“systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), ANCA-associated vasculitis, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, Chagas' disease, Grave's disease, Wegener's granulomatosis, polyarteritis nodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM multiple peripheral neuropathy, vasculitis, diabetes mellitus, Reynaud's syndrome, antiphospholipid syndrome, Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis” (¶ 120).
The specification also teaches 18 types of lymphoma, 3 types of leukemia and 2 types of plasma cell malignancies that are encompassed by the claims (¶ 120). Thus, the claims are genus claims because they are directed to treating, preventing and/or diagnosing a genus of diseases.
The specification provides a set of working examples in support of the claimed invention. Included in these is Example 7, starting at page 34, which teaches that administration of T-cells expressing a chimeric antigen receptor (CAR) comprising the anti-BCMA sdAb are able to suppress tumors in an animal model. These tumors are produced using K562-BCMA cells, a non-BCMA-expressing leukemia cell line engineered to express BCMA (page 2051 of Carpenter et al, 2013. Clin Cancer Res. 19(8): 2048-60). This resulting in tumors modeling BCMA-expressing cancer such as multiple myeloma (MM). The specification teaches that “[t]he tumor progression of each group of mice treated with humanized BCMA CAR-T Cells was controlled and alleviated to varying degrees, and at least one of the surviving mice showed tumor-free survival” (¶ 180). Thus, the working examples of the specification are limited to a single species of the genus of diseases encompassed by the claims. The relevant art at the time of filing also supports targeting BCMA for treatment and diagnosis of multiple myeloma; e.g., Dogan et al (2013; cited above) as part of a systematic literature review teaches that “the effects of BCMA expression have been studied extensively in multiple myeloma (MM), and BCMA can be targeted to achieve anti-tumor effects in MM patients” (page 1) and that soluble BCMA has been identified “as a biomarker that can monitor and predict outcomes for MM patients” (page 8). Dogon further teaches that one study identified that “plasma cell neoplasms” including those from MM and plasmacytoma samples, had “high BCMA expression levels”, with “97% of plasma cell neoplasms” being BCMA positive (page 7). As such, at the time of filing the relevant prior art would have enabled the person of ordinary skill in the art to use the claimed anti-BCMA sdAb for treatment or diagnosis of plasma cell malignancy as recited in claim 26 in the alternative and encompassed by claim 25.
However, with respect to lymphoma, leukemia and autoimmune disease, each of which is a subgenus encompassing multiple species of disease, the specification does not provide any working examples of treating such diseases with the claimed anti-BCMA antibody. Furthermore, the relevant art teaches that more research is needed to determine the efficacy of such treatments. Specifically, with respect to lymphoma, Dogon teaches that “BCMA expression in Hodgkin lymphoma and NHL varied across studies, and further research is needed to determine the utility of BCMA as an antibody target and biomarker in these disease” (see Abstract). Likewise, with respect to leukemia, Dogon teaches that “further research is warranted to determine whether anti-BCMA therapies can be effective in these malignancies” (page 11). Dogon concludes that “[f]urther research is needed to determine the utility of BCMA as a biomarker and antibody target in hematologic malignancies for which evidence was conflicting or only 1 or a few studies were conducted” (page 12). Finally, the claims also encompass a large range of autoimmune diseases having widely different causes (e.g., inflammatory bowel disease and diabetes), without the specification or relevant art providing evidence that such a range of autoimmune diseases can be effectively treated and/or diagnosed with an anti-BCMA antibody.
Thus, it remains unpredictable whether administration of an anti-BCMA antibody would act to treat or diagnose the range of diseases encompassed by the claimed method. The skilled artisan at the time of filing would not have considered the working examples to provide support for predictability in practicing the method of the claims. While enablement does not necessarily require a working example, "[l]ack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art", per MPEP 2164.02. Thus, in order to practice the claimed method, the skilled artisan would first need to engage in experimentation to determine whether administration of an anti-BCMA antibody would in fact provide treatment and/or diagnosis of the stated disease, and such experimentation, even to validate the use of a single antibody therapeutic in a single disease, would be undue in view of the amount of effort and time required. The outcome of such a study would generally be the focus of an entire publication in the relevant literature.
Due to the large quantity of experimentation necessary to determine whether an anti-BCMA antibody can be administered to treat “a disease related to BCMA expression”, including the full range of autoimmune disease, lymphoma and leukemia encompassed by the claims, the lack of guidance presented in the specification as to the predictability of whether such treatment and/or diagnosis will work, the absence of working examples demonstrating predictability of the claimed method of treatment and/or diagnosis, the complex nature of the invention, the state of the prior art which establishes unpredictability (by stating that further research is necessary), and the breadth of the claims with respect to the species of diseases to be treated and/or diagnosed, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Note on Patentability
No prior art has been identified that teaches or suggests an anti-BCMA single domain antibody of independent claim 1; specifically one that comprises three complementarity-determining regions (CDR1-3), wherein CDR1 is selected from SEQ ID NO: 1, 4 and 7; CDR2 is selected from SEQ ID NO: 2 and 5; and CDR3 is selected from SEQ ID NO: 3 and 6. These CDRs are from antibodies BH59, BH60, BH80-84, BH86 and BH87 disclosed at page 28 of the specification. The remaining pending claims depend from claim 1 and are thus free of the prior art for the same reasons.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674