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 .
Claim Objections
Claims 37-40 and 47 are objected to because of the following informalities:
All claims require a period at the end. Claims 37-40 are lacking a period following the table.
Claim 38 recites “2-12” in column 1 row 4 of the table and should recite “5-12”.
Claim 47 line 5 recites “premeditation” which should be “premedication”.
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 1-49 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.
Claims 1-5, 8-10, 12, 13, 15, 17, 22-28, 30, 32, 36, and 47 contain the trademark/trade names PF-06863135 and PF06863135. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe elranatamab and, accordingly, the identification/description is indefinite.
PF-06863135 and PF06863135 are internal corporate identifiers of an anti-BCMAxCD3 antibodies identified by the nonproprietary name elranatamab. At present, the claims switch between PF-06863135, PF06863135, and elranatamab creating further indefiniteness. Replacement of PF-06863135 and PF06863135 with the nonproprietary name elranatamab would remedy the indefiniteness.
Additionally, claims 1, 5, 7, 11 recite doses by amount and frequency or first treatment dosing by amount or frequency, but do not require a minimum duration. It is unclear if more than one dose is needed to meet the claim.
Similarly, claims 9, 10, 14, 16, and 17 recite a second treatment dosing without a minimum duration. Does a single dose less than the first treatment dosing after cycle 1 meet the second treatment dosing? Also, claim 15 recites a second treatment dosing without a duration. Does a single 76 mg Q2W dose satisfy the second treatment dosing in the claim?
Claims 18-21 recite second and/or third treatment dosing, defined as dose amount and dose frequency on page 48 of the Specification, but require no duration or number of cycles, defined as 21 or 28 days on page 48 of the Specification, required for the third treatment dosing. There’s no requirement in the claims that the second and third treatment dosing differ in amount or frequency. If a patient is given two of the same dose, for example 152 mg Q3W SC, after cycle 6, then does that satisfy the second and third treatment dosings? How does one distinguish the second and third treatment dosing when the dose amounts and frequencies have considerable overlap and there’s no requirement that the second and third treatment dosings differ from one another. For example, in the 152 mg Q3W example above, is that a second and third treatment dosing or is that merely continuing the second treatment dosing? And if there’s no minimum duration for the second treatment dosing, then how does one know whether the second 152 mg Q3W dose is part of the second treatment dosing or a continuation of second treatment dosing in place of the third treatment dosing?
Claims 22, 23, 25, 27, 32-34, and 36-40 recite dose amounts and frequencies in tables which include a number of weeks. It is unclear if the claim requires all rows or “Week Numbers” to be completed? For example, in claims 27 table (a), does one have to reach Week 25 to satisfy the claim? If the subject was only administered to Week 24, then is the claim satisfied?
Claim 30 refers to cycles and it is unclear how the cycles fit into the table in claim 22.
Claim 10 recites the limitation "the second treatment dosing" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 10 depends from claim 8 while second treatment dosing is first recited in claim 9.
Claims 6, 7, 11, 14, 16, 18-21, 24, 26, 27, 29, 31, 41-46, 48, and 49 are rejected for depending from claims 1, 5, 15, 22, 25, or 32 and fail to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(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 pre-AIA 35 U.S.C. 112, fourth 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 11 and 29 are 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 11 depends from claim 5. Both claims 5 and 11 recite 76 Q1W SC as alternative options for the first treatment dosing. If 76 Q1W SC is elected in both claims 5 and 11, then claim 11 does not further limit.
Claim 29 while depending what are priming and first treatment dosing in the Table of claim 22 fails to further limit claim 22. There is no further action required nor reduction of dose amounts or frequencies recited in claim 29.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 42, 44, and 48 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kuo et al. (US 9,969,809 B2; Published: May 15, 2018).
Kuo et al. teaches the BCMAxCD3 antibody elranatamab comprising a BCMA binding site comprising SEQ ID NOs: 357 and 358, which comprises sequences identical to instant SEQ ID NOs: 23-25 and 17, 18, and 19, and a CD3 binding site comprising SEQ ID NOs: 323 and 324, which comprise sequences identical to instant SEQ ID NOs: 4, 6, and 7; and 10, 11, and 12; see column 83 and Table 3.
Regarding claim 1 item (a), Kuo et al. teaches administering elranatamab at 1 mg/kg or 1000 μg/kg weekly; see column 151 lines 1-2. Kuo et al. teaches treat cancer comprising administering the BCMAxCD3 bispecific antibody; see columns 146-148. Regarding claim 42, Kuo et al. teaches treating multiple myeloma; see column 149 line 25. The BCMAxCD3 bispecific antibody may be administered subcutaneously; see and column 150 line 49. Regarding claims 44 and 48, Kuo et al. teaches combining elranatamab with a second therapeutic agent, including lenalidomide; see column 149 lines 24-49.
Thus, Kuo et al. anticipates claims 1, 42, 44, and 48.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-49 are rejected under 35 U.S.C. 103 as being unpatentable over Kuo et al. (US 9,969,809 B2; Published: May 15, 2018) in view of Daley et al. (WO 2018/201051 A1; Published: November 1, 2018), Baldwin et al. (WO 2017/031104 A1; Published: February 23, 2017), Brownstein et al. (US 2020/0129617 A1; Published: April 30, 2020), Mikhael et al. (Leukemia. 34: 3298-3309; Published: May 14, 2020), and Sanchez-Felix et al. (Advanced Drug Delivery Reviews. 167: 66-67; Published Online: May 27, 2020).
Note that claim 1 is included in this rejection under U.S.C. 103 to reject the dose amounts and frequencies recited and not addressed above.
Kuo et al. teaches the BCMAxCD3 antibody elranatamab comprising a BCMA binding site comprising SEQ ID NOs: 357 and 358, which comprises sequences identical to instant SEQ ID NOs: 23-25 and 17, 18, and 19, and a CD3 binding site comprising SEQ ID NOs: 323 and 324, which comprise sequences identical to instant SEQ ID NOs: 4, 6, and 7; and 10, 11, and 12; see column 83 and Table 3.
Kuo et al. teaches treat cancer comprising administering the BCMAxCD3 bispecific antibody; see columns 146-148. Regarding claim 42, Kuo et al. teaches treating multiple myeloma; see column 149 line 25. The BCMAxCD3 bispecific antibody may be administered subcutaneously; see column 149 line 61 and column 150 line 49. Kuo et al. teaches a dose range from about 3 μg/kg to 100 mg/kg or more; see column 150 lines 55-61.
Regarding priming doses, Kuo et al. teaches about initial doses (i.e. priming doses) which may be greater or lesser than the subsequent maintenance doses; see column 151 lines 1-7.
Regarding dose frequency, Kuo et al. teaches administering the bispecific antibody one to four times a week, weekly, every other week, once a month, once every other month, or once every three months; see column 151 lines 1-14.
Regarding combination regimens of claims 44, 48, and 49, Kuo et al. teaches administering the BCMAxCD3 bispecific antibody in combination with lenalidomide, radiation, or a second antibody; see column 149 line 46 and column 148 lines 59 and 67.
Kuo et al. does not teach administering every three weeks, a second treatment dosing comprising less frequent or lower doses than the first treatment dosing, nor the duration of treatment. While Kuo et al. teaches administering a second antibody in combination, the reference does not teach that that antibody is sasanlimab, daratumumab, nor isatuximab. And, while Kuo et al. teaches initial doses (i.e. priming doses), the reference does not teach administering more than one initial dose in the first week. Kuo et al. does not teach premedication. Regarding claim 1 specifically, while Kuo et al. teaches 1000 ug/mg Q1W, as noted in the rejection under U.S.C. 102 above, and dose ranges and frequencies, Kuo et al. does not teach another embodiment comprising a dose frequency and dose amount recited in claim 1.
Daley et al. teaches administering a BCMAxCD3 bispecific subcutaneously with dose ranges from 1-40 mg/kg and at a frequency of weekly, to once every 2, 3, or 4 weeks; see page 152 lines 17-21. Regarding claims 43 and 45, Daley et al. teaches the method of treating a disease associated with BCMA comprising administering a BCMAxCD3 bispecific antibody and a PD-1 inhibitor, PF-06801591 (i.e. sasanlimab) or an ADCC-competent antibody (e.g. daratumumab); see claim 74.
Neither Kuo et al. nor Daley et al. teach administering a BCMAxCD3 bispecific antibody as fixed dose, the use of premedication, nor first, second or third treatment dosing.
Baldwin et al. teaches administering a BCMAxCD3 antibody as fixed dose using mg/kg based on an estimated body weight of 70 kg to calculate the fixed dose; see page 53. Additionally, Balwin et al. teaches that maintenance therapy with the BCMAxCD3 antibody may be for a period of six months or more; see page 54 line 4.
Neither Kuo et al., Daley et al., nor Baldwin et al. teach the use of premedication nor first, second or third treatment dosing.
Brownstein et al. teaches dosing strategies for T-cell activating bispecific antibodies, including BCMAxCD3 bispecific antibodies, to reduce the incidence of cytokine release syndrome (CRS). Brownstein et al. teaches pretreatment use or administered in combination with a steroid (e.g. dexamethasone); see paragraph 0105. Further, regarding priming doses, Brownstein et al. teaches administering the therapeutic dose as 2-5 fractions of a single dose amount during the first week or two weeks of treatment and administering a single dose in weeks 3 or 4 through week 14; see paragraphs 0075 and 0081 and claims 1, 2, 4, 6, 10, and 5. Additionally, regarding first, second, and third treatment dosing, Brownstein et al. teaches switching from weekly dosing to dosing once every two weeks, one every three weeks, or one every four weeks during a maintenance phase which follows the weekly phase; see claims 18 and 19.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer, including multiple myeloma, by administering the BCMAxCD3 antibody, elranatamab because Kuo et al. teaches administering elranatamab to treat cancer, including multiple myeloma. Further, regarding claims 43-46, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer with a combination of elranatamab and lenalidomide, daratumumab, isatuximab, sasanlimab or radiation therapy because Kuo et al. teaches combining elranatamab with lenalidomide, radiation, or a second antibody and Daley et al. teaches treating cancer with a combination of a BCMAxCD3 antibody and daratumumab or sasanlimab.
Regarding isatuximab in claim 46, isatuximab, like daratumumab, is a CD38 antibody and was known to be used in the treatment of cancer, including multiple myeloma as taught by Mikhael et al. Given that isatuximab and daratumumab have similar mechanisms of action it would have been obvious to substitute isatuximab in place of daratumumab and one would have had a reasonable expectation of success to do so.
Regarding the use of a premedication in claim 47, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administered a pretreatment, such as dexamethasone, either prior to the administration of or in combination with the elranatamab because Brownstein et al. teaches that CD3 targeting bispecific antibodies, including BCMAxCD3 antibodies, can trigger CRS and teaches the use of premedication to reduce the risk of CRS.
Finally, claims 1-41 recite various dosing regimens. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Indeed, Kuo et al., which teaches the antibody elranatamab, states that “[o]ther dosage regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. […] The progress of this therapy is easily monitored by conventional techniques and assays. The dosing regimen (including the antibody ( e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used) can vary over time. For the purpose of the present invention, the appropriate dosage of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate will depend on the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate ( or compositions thereof) employed, the type and severity of symptoms to be treated, whether the agent is administered for therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, the patient's clearance rate for the administered agent, and the discretion of the attending physician. Typically, the clinician will administer an antibody ( e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate until a dosage is reached that achieves the desired result. Dose and/or frequency can vary over course of treatment. Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage.” Thus, Kuo et al. acknowledges that it is well within the prevue of one of ordinary skill in the art to optimize the dosing regimen of elranatamab by routine and conventional experimentation.
In addition to be within the prevue of one of ordinary skill in the art to optimize, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer elranatamab as a fixed dose subcutaneously because Kuo et al. teaches subcutaneous administration of elranatamab and Baldwin et al. teaches administering fixed doses of a BCMAxCD3 antibody. One would have been motivated to administer elranatamab as a fixed subcutaneous dose for ease of use. Fixed dose, subcutaneously administered medications could enable the patient to administer their medication at home without the risk of erroneously calculating a body weight dose; see Sanchez-Felix et al. The convenience of potential out-of-clinic dosing could drive increased market share in the BCMAxCD3 space over elranatamab competitors limited to body weight based IV infusion administered BCMAxCD3 antibodies which would require a clinic visit to administer.
Similarly, regarding priming doses and the second and third treatment regimens (i.e. extended frequency dosing or reduced doses), while also being within the prevue of one of ordinary skill in the art to optimize through routine experimentation, Brownstein et al. teaches administering the initial doses as fractions of the later therapeutic dose and transitioning the patient onto an extended frequency maintenance dosing phase following the weekly administered dosing phase. Given that Brownstein et al. teaches this dosing regimen in order to reduce the risk of CRS associated with T cell-activating cancer immunotherapies, including BCMAxCD3 bispecific antibodies, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to incorporate the priming doses and later extended frequency dosing into the regimen for treating cancer by administering elranatamab into order to reduce the potential development of CRS. The mitigation of CRS risk is particularly meaningful for a T cell-activating immunotherapy with the potential to be administered out of clinic (i.e. a fixed dose subcutaneously administered elranatamab).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
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 1-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,969,809 B2 in view of Daley et al. (WO 2018/201051 A1; Published: November 1, 2018), Baldwin et al. (WO 2017/031104 A1; Published: February 23, 2017), Brownstein et al. (US 2020/0129617 A1; Published: April 30, 2020), Mikhael et al. (Leukemia. 34: 3298-3309; Published: May 14, 2020), and Sanchez-Felix et al. (Advanced Drug Delivery Reviews. 167: 66-67; Published Online: May 27, 2020).
Claims 1-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,155,630 B2 in view of Daley et al. (WO 2018/201051 A1; Published: November 1, 2018), Baldwin et al. (WO 2017/031104 A1; Published: February 23, 2017), Brownstein et al. (US 2020/0129617 A1; Published: April 30, 2020), Mikhael et al. (Leukemia. 34: 3298-3309; Published: May 14, 2020), and Sanchez-Felix et al. (Advanced Drug Delivery Reviews. 167: 66-67; Published Online: May 27, 2020).
The following analysis applies to both nonstatutory double patenting rejections over the issued claims of U.S. Patent Nos. 9,969,809 B2 and 11,155,630 B2.
Issued claims 1-5 of U.S. Patent No. 9,969,809 B2 teach a BCMAxCD3 bispecific antibody comprising VH CDRs of the CD3 binding site found in SEQ ID NO: 320 and VL CDRs of the CD3 binding site found in SEQ ID NO: 321. SEQ ID NO: 320 comprises the CDRs of instant SEQ ID NOs: 4 (residues 26-35), 5 (residues 52-59), and 7 (residues 101-110) and SEQ ID NO: 321 comprises the CDRs of instant SEQ ID NO: 10 (residues 24-40), 11 (residues 56-62), and 12 (residues 95-102). Similarly, the CDRs of the CD3 binding site comprising SEQ ID NOs: 331 or 333, 336, 335, 343, 341, and 342 are 100% identical to instant SEQ ID NOs: 2 or 4, 6, 7, 10, 11, and 12, respectively. Further, the bispecific comprises a BCMA binding site comprising the CDRs of SEQ ID NOs: 151 or 157, 159, 155, 209, 221, and 225 which are 100% identical to instant SEQ ID NOs: 15 or 17, 18, 20, 23, 24, and 25, respectively. Similarly, issued claims 1-4 of U.S. Patent No. 11,155,630 B2 teach an antibody comprising CD3 binding site CDRs of SEQ ID NOs: 333, 336, 335, 343, 341, and 342, which are 100% identical to instant SEQ ID NOs: 4, 6, 7, 10, 11, and 12, and BCMA binding site CDRs of SEQ ID NOs: 157, 158, 155, 209, 221, and 225, which are 100% identical to instant SEQ ID NOs: 17, 18, 20, 23, 24, and 25, and wherein SEQ ID NO: 159 is a subsequence of SEQ ID NO: 158, the latter being 100% identical to instant SEQ ID NO: 19. These CDRs are associated with elranatamab, also known as PF-06863135, as evidenced by Table 19 in the instant Specification.
MPEP 804(II)(B)(1) states that “it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context.” See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
Consistent with Sun Pharm., it is permissible to use a compound claim to reject a method of use claim where that method of use is disclosed in the specification of the application claiming the compound.
In this case, the specification of the reference application (column 8 lines 38-44 of U.S. Patent No. 9,969,809 B2 or column 8 lines 46-52 of U.S. Patent No. 11,155,630 B2) also discloses that the BCMAxCD3 bispecific antibody, known as elranatamab, may be used for treatment of cancer:
Also provided are methods of treating a condition associated with malignant cells expressing a tumor antigen in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical compositions of the invention. In some embodiments, the condition is cancer. In some embodiments, the cancer is a B-cell related cancer selecting from the group consisting of multiple myeloma […].
Accordingly, when the claims of the reference application are properly construed using its accompanying specification, the claimed method of treating cancer is obvious over the claims to the elranatamab pharmaceutical composition, since this same utility elranatamab is disclosed in the specification of the reference application.
The issued claims do not teach subcutaneous administration, a dosage, a dose frequency, a second treatment dosing comprising less frequent or lower doses than the first treatment dosing, the duration of treatment, combination with lenalidomide, radiation, sasanlimab, daratumumab, nor isatuximab, nor the use of premedication.
Daley et al. teaches administering a BCMAxCD3 bispecific subcutaneously with dose ranges from 1-40 mg/kg and at a frequency of weekly, to once every 2, 3, or 4 weeks; see page 152 lines 17-21. Regarding instant claims 43 and 45, Daley et al. teaches the method of treating a disease associated with BCMA comprising administering a BCMAxCD3 bispecific antibody and a PD-1 inhibitor, PF-06801591 (i.e. sasanlimab) or an ADCC-competent antibody (e.g. daratumumab); see claim 74. Additionally, regarding instant claims 44, 48, and 49, Daley et al. teaches that the BCMAxCD3 antibody may be used in combination with radiation, lenalidomide, or a second therapeutic agent; see page 164.
Neither the issued claims nor Daley et al. teach administering a BCMAxCD3 bispecific antibody as fixed dose, the use of premedication, nor first, second or third treatment dosing.
Baldwin et al. teaches administering a BCMAxCD3 antibody as fixed dose using mg/kg based on an estimated body weight of 70 kg to calculate the fixed dose; see page 53. Additionally, Balwin et al. teaches that maintenance therapy with the BCMAxCD3 antibody may be for a period of six months or more; see page 54 line 4.
Neither the issued claims, Daley et al., nor Baldwin et al. teach the use of premedication nor first, second or third treatment dosing.
Brownstein et al. teaches dosing strategies for T-cell activating bispecific antibodies, including BCMAxCD3 bispecific antibodies, to reduce the incidence of cytokine release syndrome (CRS). Brownstein et al. teaches pretreatment use or administered in combination with a steroid (e.g. dexamethasone); see paragraph 0105. Further, regarding priming doses, Brownstein et al. teaches administering the therapeutic dose as 2-5 fractions of a single dose amount during the first week or two weeks of treatment and administering a single dose in weeks 3 or 4 through week 14; see paragraphs 0075 and 0081 and claims 1, 2, 4, 6, 10, and 5. Additionally, regarding first, second, and third treatment dosing, Brownstein et al. teaches switching from weekly dosing to dosing once every two weeks, one every three weeks, or one every four weeks during a maintenance phase which follows the weekly phase; see claims 18 and 19.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer, including multiple myeloma, by administering the BCMAxCD3 antibody, elranatamab because U.S. Patent Nos. 9,969,809 B2 or 11,155,630 B2 teaches administering elranatamab to treat cancer, including multiple myeloma. Further, regarding instant claims 43-46, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer with a combination of elranatamab and lenalidomide, daratumumab, isatuximab, sasanlimab or radiation therapy because Daley et al. teaches combining elranatamab with lenalidomide, radiation, or a second therapeutic agent, daratumumab or sasanlimab.
Regarding isatuximab in instant claim 46, isatuximab, like daratumumab, is a CD38 antibody and was known to be used in the treatment of cancer, including multiple myeloma as taught by Mikhael et al. Given that isatuximab and daratumumab have similar mechanisms of action it would have been obvious to substitute isatuximab in place of daratumumab and one would have had a reasonable expectation of success to do so.
Regarding the use of a premedication in instant claim 47, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administered a pretreatment, such as dexamethasone, either prior to the administration of or in combination with the elranatamab because Brownstein et al. teaches that CD3 targeting bispecific antibodies, including BCMAxCD3 antibodies, can trigger CRS and teaches the use of premedication to reduce the risk of CRS.
Finally, instant claims 1-41 recite various dosing regimens. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Indeed, U.S. Patent No. 9,969,809 B2 (column 151) or 11,155,630 B2 (column 152) states that “[o]ther dosage regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. […] The progress of this therapy is easily monitored by conventional techniques and assays.The dosing regimen (including the antibody ( e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used) can vary over time. For the purpose of the present invention, the appropriate dosage of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate will depend on the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate ( or compositions thereof) employed, the type and severity of symptoms to be treated, whether the agent is administered for therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, the patient's clearance rate for the administered agent, and the discretion of the attending physician. Typically, the clinician will administer an antibody ( e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate until a dosage is reached that achieves the desired result. Dose and/or frequency can vary over course of treatment. Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage.” Thus, U.S. Patent Nos. 9,969,809 B2 or 11,155,630 B2 acknowledge that it is well within the prevue of one of ordinary skill in the art to optimize the dosing regimen of elranatamab by routine and conventional experimentation.
In addition to be within the prevue of one of ordinary skill in the art to optimize, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer elranatamab as a fixed dose subcutaneously because Daley et al. teaches subcutaneous administration of elranatamab and Baldwin et al. teaches administering fixed doses of a BCMAxCD3 antibody. One would have been motivated to administer elranatamab as a fixed subcutaneous dose for ease of use. Fixed dose, subcutaneously administered medications could enable the patient to administer their medication at home without the risk of erroneously calculating a body weight dose; see Sanchez-Felix et al. The convenience of potential out-of-clinic dosing could drive increased market share in the BCMAxCD3 space over elranatamab competitors limited to body weight based IV infusion administered BCMAxCD3 antibodies which would require a clinic visit to administer.
Similarly, regarding priming doses and the second and third treatment regimens (i.e. extended frequency dosing or reduced doses), while also being within the prevue of one of ordinary skill in the art to optimize through routine experimentation, Brownstein et al. teaches administering the initial doses as fractions of the later therapeutic dose and transitioning the patient onto an extended frequency maintenance dosing phase following the weekly administered dosing phase. Given that Brownstein et al. teaches this dosing regimen in order to reduce the risk of CRS associated with T cell-activating cancer immunotherapies, including BCMAxCD3 bispecific antibodies, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to incorporate the priming doses and later extended frequency dosing into the regimen for treating cancer by administering elranatamab into order to reduce the potential development of CRS. The mitigation of CRS risk is particularly meaningful for a T cell-activating immunotherapy with the potential to be administered out of clinic (i.e. a fixed dose subcutaneously administered elranatamab).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,793,635 B2 in view of Daley et al. (WO 2018/201051 A1; Published: November 1, 2018), Baldwin et al. (WO 2017/031104 A1; Published: February 23, 2017), Brownstein et al. (US 2020/0129617 A1; Published: April 30, 2020), Mikhael et al. (Leukemia. 34: 3298-3309; Published: May 14, 2020), and Sanchez-Felix et al. (Advanced Drug Delivery Reviews. 167: 66-67; Published Online: May 27, 2020).
Regarding elranatamab, also known as PF-06863135, in instant claims 1-49, issued claims 1-13 teach methods of treating a condition associated with malignant cells expressing BCMA or multiple myeloma, inhibiting the metastasis of malignant cells expressing BCMA, inhibiting tumor growth or progression in a subject with malignant cells expressing BCMA, or inducing tumor regression in a subject with malignant cells expressing BCMA comprising administering a BCMAxCD3 bispecific antibody comprising VH CDRs of the CD3 binding site found in SEQ ID NO: 320 and VL CDRs of the CD3 binding site found in SEQ ID NO: 321. SEQ ID NO: 320 comprises the CDRs of instant SEQ ID NOs: 4 (residues 26-35), 5 (residues 52-59), and 7 (residues 101-110) and SEQ ID NO: 321 comprises the CDRs of instant SEQ ID NO: 10 (residues 24-40), 11 (residues 56-62), and 12 (residues 95-102). Similarly, the CDRs of the CD3 binding site comprising SEQ ID NOs: 331 or 333, 336, 335, 343, 341, and 342 are 100% identical to instant SEQ ID NOs: 2 or 4, 6, 7, 10, 11, and 12, respectively. Further, the bispecific comprises a BCMA binding site comprising the CDRs of SEQ ID NOs: 151 or 157, 159, 155, 209, 221, and 225 which are 100% identical to instant SEQ ID NOs: 15 or 17, 18, 20, 23, 24, and 25, respectively. These CDRs are associated with elranatamab, also known as PF-06863135, as evidenced by Table 19 in the instant Specification.
The issued claims do not teach subcutaneous administration, a dosage, a dose frequency, a second treatment dosing comprising less frequent or lower doses than the first treatment dosing, the duration of treatment, combination with lenalidomide, radiation, sasanlimab, daratumumab, nor isatuximab, nor the use of premedication.
Daley et al. teaches administering a BCMAxCD3 bispecific subcutaneously with dose ranges from 1-40 mg/kg and at a frequency of weekly, to once every 2, 3, or 4 weeks; see page 152 lines 17-21. Regarding instant claims 43 and 45, Daley et al. teaches the method of treating a disease associated with BCMA comprising administering a BCMAxCD3 bispecific antibody and a PD-1 inhibitor, PF-06801591 (i.e. sasanlimab) or an ADCC-competent antibody (e.g. daratumumab); see claim 74. Additionally, regarding instant claims 44, 48, and 49, Daley et al. teaches that the BCMAxCD3 antibody may be used in combination with radiation, lenalidomide, or a second therapeutic agent; see page 164.
Neither the issued claims nor Daley et al. teach administering a BCMAxCD3 bispecific antibody as fixed dose, the use of premedication, nor first, second or third treatment dosing.
Baldwin et al. teaches administering a BCMAxCD3 antibody as fixed dose using mg/kg based on an estimated body weight of 70 kg to calculate the fixed dose; see page 53. Additionally, Balwin et al. teaches that maintenance therapy with the BCMAxCD3 antibody may be for a period of six months or more; see page 54 line 4.
Neither the issued claims, Daley et al., nor Baldwin et al. teach the use of premedication nor first, second or third treatment dosing.
Brownstein et al. teaches dosing strategies for T-cell activating bispecific antibodies, including BCMAxCD3 bispecific antibodies, to reduce the incidence of cytokine release syndrome (CRS). Brownstein et al. teaches pretreatment use or administered in combination with a steroid (e.g. dexamethasone); see paragraph 0105. Further, regarding priming doses, Brownstein et al. teaches administering the therapeutic dose as 2-5 fractions of a single dose amount during the first week or two weeks of treatment and administering a single dose in weeks 3 or 4 through week 14; see paragraphs 0075 and 0081 and claims 1, 2, 4, 6, 10, and 5. Additionally, regarding first, second, and third treatment dosing, Brownstein et al. teaches switching from weekly dosing to dosing once every two weeks, one every three weeks, or one every four weeks during a maintenance phase which follows the weekly phase; see claims 18 and 19.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer, including multiple myeloma, by administering the BCMAxCD3 antibody, elranatamab because U.S. Patent No. 10,793,635 B2 teaches administering elranatamab to treat cancer, including multiple myeloma. Further, regarding instant claims 43-46, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer with a combination of elranatamab and lenalidomide, daratumumab, isatuximab, sasanlimab or radiation therapy because Daley et al. teaches combining elranatamab with lenalidomide, radiation, or a second therapeutic agent, daratumumab or sasanlimab.
Regarding isatuximab in instant claim 46, isatuximab, like daratumumab, is a CD38 antibody and was known to be used in the treatment of cancer, including multiple myeloma as taught by Mikhael et al. Given that isatuximab and daratumumab have similar mechanisms of action it would have been obvious to substitute isatuximab in place of daratumumab and one would have had a reasonable expectation of success to do so.
Regarding the use of a premedication in instant claim 47, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administered a pretreatment, such as dexamethasone, either prior to the administration of or in combination with the elranatamab because Brownstein et al. teaches that CD3 targeting bispecific antibodies, including BCMAxCD3 antibodies, can trigger CRS and teaches the use of premedication to reduce the risk of CRS.
Finally, instant claims 1-41 recite various dosing regimens. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Indeed, U.S. Patent No. 10,793,635 B2 (columns 147-148) states that “[o]ther dosage regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. […] The progress of this therapy is easily monitored by conventional techniques and assays.The dosing regimen (including the antibody ( e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used) can vary over time. For the purpose of the present invention, the appropriate dosage of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate will depend on the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate ( or compositions thereof) employed, the type and severity of symptoms to be treated, whether the agent is administered for therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, the patient's clearance rate for the administered agent, and the discretion of the attending physician. Typically, the clinician will administer an antibody ( e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate until a dosage is reached that achieves the desired result. Dose and/or frequency can vary over course of treatment. Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage.” Thus, U.S. Patent No. 10,793,635 B2 acknowledges that it is well within the prevue of one of ordinary skill in the art to optimize the dosing regimen of elranatamab by routine and conventional experimentation.
In addition to be within the prevue of one of ordinary skill in the art to optimize, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer elranatamab as a fixed dose subcutaneously because Daley et al. teaches subcutaneous administration of elranatamab and Baldwin et al. teaches administering fixed doses of a BCMAxCD3 antibody. One would have been motivated to administer elranatamab as a fixed subcutaneous dose for ease of use. Fixed dose, subcutaneously administered medications could enable the patient to administer their medication at home without the risk of erroneously calculating a body weight dose; see Sanchez-Felix et al. The convenience of potential out-of-clinic dosing could drive increased market share in the BCMAxCD3 space over elranatamab competitors limited to body weight based IV infusion administered BCMAxCD3 antibodies which would require a clinic visit to administer.
Similarly, regarding priming doses and the second and third treatment regimens (i.e. extended frequency dosing or reduced doses), while also being within the prevue of one of ordinary skill in the art to optimize through routine experimentation, Brownstein et al. teaches administering the initial doses as fractions of the later therapeutic dose and transitioning the patient onto an extended frequency maintenance dosing phase following the weekly administered dosing phase. Given that Brownstein et al. teaches this dosing regimen in order to reduce the risk of CRS associated with T cell-activating cancer immunotherapies, including BCMAxCD3 bispecific antibodies, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to incorporate the priming doses and later extended