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 .
Response to Amendment
The Amendment filed August 27, 2025 in response to the Office Action of February 27, 2025 is acknowledged and has been entered.
Claims 1, 8-10, 12, 19, 35, 55, 90, 92, 125-126, 197-198, 222, and 228-232 are currently under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Rejections Maintained
Claim(s) 126 and 197 remain rejected under 35 U.S.C. 102(a)(2) as being anticipated by Daly et al., (US20200179511).
Applicants argue (remarks, page 1, 08/27/2025) that the prior art’s disclosure of a dose range of about 1 to 40mg/kg is not a disclosure of a “1 mg/kg” dose. This argument has been considered but is not found persuasive. Claim 126 provides a range of dosages with the upper end “about” 600 or 900 or 1000 or 1200 ug/kg. Thus, the prior art’s lower range of 1mg (same as 1000 ug) is clearly consistent with the claimed upper ranges of about 900ug, about 1000ug and about 1200 ugs. Also, the prior art teaches [0553], “An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a BCMA-targeting agent (e.g., an anti-BCMA antibody molecule or a recombinant non-antibody protein that binds to BCMA) is 0.1-30 mg/kg. Thus, an alternative lower range begins at 100ug/k which is well within the any of the claimed ranges. "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023).
Rejections Withdrawn
All rejections under 35 USC 103 made in the non-final rejection mailed 02/27/2025 are withdrawn. Applicants argued that Abujoub is not prior art because the claims under examination and the subject matter disclosed in Abujoub were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claims under examination.
New Rejections
Claim(s) 126, 197, 229-231 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/201051 (Daley et al, November 1, 2018, Applicant’s IDS).
Daley teaches a method of treating a disease associated with BCMA expression comprising administering a bispecific antibody having specificity towards BCMA and a T-cell (See claim 2, page 201 of WO document). The reference further teaches (page 152) an exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a BCMA-targeting agent (e.g., an anti-BCMA antibody molecule or a recombinant non-antibody protein that binds to BCMA) is 0.1-30 mg/kg which is equivalent to 100 ug - 30,000 ug/kg. This anticipates any of the claimed ranges. "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). Daly et al. further teach that disease associated with BCMA expression is cancer. The cancer can also be a “hematological” (blood) cancer. The reference further teaches that the disease associated with BCMA expression is multiple myeloma (See claim 67 of WIPO document).
Claim Rejections - 35 USC § 103
Claim(s) 222, 228, and 232 is/are also rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/201051 (Daley et al, November 1, 2018) in view of Kang et al. (BioProcess Intl, 14(4) April 2016) and Chim et al. (Leukemia, 32, 2018).
Regarding pharmaceutical formulations, Daly et al teach (page 151, line 12) as set forth above and also teach that the BCMA-targeting agents (e.g., an anti-BCMA antibody molecule or a recombinant non-antibody protein that binds to BCMA) can be administered by intravenous infusion to reach a dose of about 10 mg/m2. The units of does per surface area can be converted to concentration (10mg/ml). Daly further teaches that pharmaceutically acceptable carriers include any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g. by injection or infusion). Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high protein concentration. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a BCMA-targeting agent) in the required amount in an appropriate solvent with one or a combination of ingredients. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a BCMA-targeting agent) in the required amount in an appropriate solvent with one or a combination of ingredients followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle (encompasses a “vial”) that contains a basic dispersion medium and other required ingredient. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
Daly does not specifically teach that the pharmaceutical composition comprises histidine or 20mM histidine, sucrose or 240 mM sucrose, and PS20 or 0.04% PS20. Daly also does not teach a pH of about 5.5 +/- 0.3. Also, Daly does not specifically teach that the multiple myeloma is “relapsed” or “refractory” multiple myeloma.
Kang et al. teach (first page) a rich database of successful MAb formulations from 37 formulations that have been used successfully in commercial MAbs. This included common buffers such as histidine and citrate which keep pH levels between 4.7 and 7.4. 80% of the formulations used one of three surfactants: PS80, PS20, and poloxamer 188. Further, sucrose was the most popular excipient and was included in over 80% of the formulations. Also see Table 1 (page 42).
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to formulate the antibodies of Daly into pharmaceutical compositions by including the common excipients and buffers for antibodies as taught by Kang et al. One would have been motivated to do so for the purposes of successfully packaging the antibodies for proper storage and stability and to permit the proper dosage for clinical suitability. MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses.
Further, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to include patients with relapsed and/or refractory multiple myeloma (MM) because it is well known in the art that relapse is common in MM patients. For example, Chim et al. teach (page 252) that despite enormous advances with the advent of proteasome inhibitors (PI) and immunomodulatory agents (IMiDs), management of multiple myeloma (MM) remains challenging, and relapse of MM and disease progression is common even after achievement of a complete remission. Further, clinically, significant activity of monoclonal antibodies in relapsed/refractory myeloma has been demonstrated in multiple human studies (page 256-257, under “Major Clinical Trials of Monoclonal Antibodies”).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-10, 12, 19, 35, 55, 90, 92, 125-126, 197,198, 222, 228-232 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of U.S. Patent No. 11492409 in view of Kang et al. (BioProcess Intl, 14(4) April 2016).
Patented claim 26 is drawn to:
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The above binding molecule is 100% identical to the bispecific molecule used in the pending claims. SEQ ID NO:509 is 100% identical to SEQ ID NO:1, SEQ ID NO: 510 is 100% identical to SEQ ID NO:2, and SEQ ID NO:504 is 100% identical to SEQ ID NO:3. While the patented claims do not set forth a method of treating a subject suffering from a disease associated with BCMA expression (e.g., cancer, blood cancer, multiple myeloma, or refractory/relapsed multiple myeloma), portions of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. In the instant case, this would include methods of administration, routes of delivery, and combinatorial treatments. Further, regarding pending claim 126, the patent teaches treatment with bivalent BCMA-CD3 AB1 at 0.3 mg/kg and 3.0 mg/kg resulted in significant tumor regressions. 0.3mg is equivalent to 300ug which is within the dose ranges of pending claim 19, and 126. Further, regarding pending claims 125, 222, and 228 one of ordinary skill in the art at the time of filing would consider it prima facie obvious to formulate the patented antibodies into pharmaceutical compositions by including the common excipients and buffers for antibodies as taught by Kang et al. (See para 9 above). One would have been motivated to do so for the purposes of successfully packaging the antibodies for proper storage and stability and to permit the proper dosage for clinical suitability. MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses.
Claims1, 8-10, 12, 19, 35, 55, 90, 92, 125-126, 197,198, 222, 228-232 are also rejected on the ground of nonstatutory double patenting as being unpatentable over claim 23 of U.S. Patent No. 12275795 in view of Kang et al. (BioProcess Intl, 14(4) April 2016). Although the claims at issue are not identical, they are not patentably distinct from each other because patented claim 23 states:
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The nucleic acids encoding each of SEQ ID NO:509-510 and 504 are 100% identical to the pending claims comprising SEQ ID Nos: 1-3. It would be obvious and routine to one of ordinary skill in the art at the time the invention was made to include the nucleic acids that encode the pending claims drawn to the encoded proteins within the bispecific antibody. While the patented claims do not set forth a method of treating a subject suffering from a disease associated with BCMA expression (e.g., cancer, blood cancer, multiple myeloma, or refractory/relapsed multiple myeloma), portions of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. In the instant case, this would include methods of administration, routes of delivery, and combinatorial treatments. Further, regarding pending claim 126, the patent teaches treatment with bivalent BCMA-CD3 AB1 at 0.3 mg/kg and 3.0 mg/kg resulted in significant tumor regressions. 0.3mg is equivalent to 300ug which is within the dose ranges of pending claim 126. Further, regarding pending claims 125, 222, and 228, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to formulate the patented antibodies into pharmaceutical compositions by including the common excipients and buffers for antibodies as taught by Kang et al. (see para 9 above). One would have been motivated to do so for the purposes of successfully packaging the antibodies for proper storage and stability and to permit the proper dosage for clinical suitability. MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses.
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 126, 197-198, 229-232 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 of treating a disease associated with BCMA expression, does not reasonably provide enablement for a method of “preventing” any all diseases associated with BCMA expression including cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The focus of the enablement inquiry is whether everything within the scope of the claim(s) is/are enabled, at the time of filing, without requiring undue experimentation to make or use the invention. The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims: With respect to claim breadth, the standard under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. The claims are broadly inclusive of preventing the occurrence of cancer in a mammalian subject comprising administering a multispecific antibody with specificity towards at least BCMA and a T-cell engaging arm.
22. The state of the prior art and the level of predictability in the art: With regards to the prevention of cancer in a subject comprising administering an antibody, the specification does not disclose sufficient guidance or objective evidence that such antibodies would predictably prevent the formation of cancer cells in a mammal. The prevention of cancer, let alone the prevention of cancer with an antibody, is highly unpredictable. The majority of studies suggest that the essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. Further, such studies require the appropriate experimental models for analyzing chemo- or immunoprevention. For example, Granziero et al. (Eur. J. Immunol. 1999, 29:1127-1138) teach that many models are not suitable for testing immunotherapeutic approaches intended to cure cancer. They suggest that the optimal model (prostate cancer, in their case) would have spontaneous tumor development in its natural location (1st column, page 1128) wherein disease progression would closely resemble the progression of the particular type of cancer. Hence, depending on the type of model employed one could establish a reasonable link between antecedent drug and subsequent knowledge of the prevention of the disease. Further, reasonable guidance with respect to correlating agents that prevent cancer may depend upon quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. For example, Byers, T. (CA Journal, Vol. 49, No. 6, Nov/Dec. 1999) teaches that randomized controlled trials are commonly regarded as the definitive study for proving causality (1st col., p.358), and that in controlled trials the random assignment of subjects to the intervention eliminates the problems of dietary recalls and controls the effects of both known and unknown confounding factors. Further, Byers suggests that chemo-preventative trials be designed “long-term” such that testing occurs over many years (2nd col., p. 359). The specification is devoid of any models or experimental analysis that reasonably suggests that the claimed method would predictably prevent the formation of tumors in a mammal. This, combined with the state of the art of preventing cancer, suggests that undue experimentation would be required to practice the invention as broadly claimed.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643