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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 .
Claims 72, 76, 80-81, 85-86, and 91-92 are pending and will be examined on the merits.
Rejections/Objections Withdrawn.
All rejections of all cancelled claims are mooted by claim cancelation.
All standing NSDP 35 USC §§ 102 and 103 rejections have been withdrawn in view of claim amendments.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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 72, 76, 80-81, 85-86, and 91-92 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 72 and 86
Claims 72 and 86 are directed to PD1/CTLA4 bispecific antibodies. Claims 72 and 86 also both recite that “the bispecific antibody is monovalent”. This is directly contradictory because a “bispecific” antibody binds two distinct antigens but a “monovalent” antibody binds a single antigen only. It is unclear how any antibody can be simultaneously monovalent and bispecific, rendering the metes and bounds of the claim unclear and therefore indefinite.
Note: for the purposes of examination the claims will be examined as if the “monovalent” limitation(s) are not present.
Claims 91 and 92
Regarding claims 91 and 92, the parentheses enclosing the dosing levels recited in claims 91 and 92 render the claims indefinite because it is unclear whether the limitation(s) enclosed within the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Note: for the purposes of examination the doses enclosed within the parentheses will be treated as required limitations.
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.
Claim(s) 72, 76, 81 and 85-86 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to 7/27/2020 by way of US 63/057,054, of record) in view of Kasturirangan (Kasturirangan , et al., WO 2017/193032 A2; Published 11/9/2017; Priority to 5/6/2016 by way of US 62/332,788, of record) and Dovedi (Dovedi, et al., Cancer Discov (2021) 11(5):1100)
Sumrow teaches on dosing regimens for administering a PD-1xCTLA-4 bispecific molecules (Sumrow, Abstract). Sumrow discloses a method of treating cancer, said method comprising a PD1/CTLA4 bispecific binding molecule at a dose from about 3 mg/kg to 10 mg/kg once every three weeks (Sumrow, claim 1), wherein the cancer is NSCLC (Sumrow, Claim 25). Please note that, for an average 80 kg human, 3-10 mg/kg is the same as 240 mg/kg – 800 mg/kg (3 mg/kg * 80 kg = 240 mg and 10 mg/kg * 80 kg = 800 mg). Sumrow discloses that the PD1/CTLA4 bispecific binding molecule of Sumrow is administered in conjunction with chemotherapeutic agents (Sumrow, ¶ 152).
Regarding claims 85-86, the method of treating NSCLC tumor comprising administering the PD-1xCTLA-4 bispecific molecules would also be a method of inhibiting growth of an NSCLC tumor because cancer is an uncontrolled growth of tumor cells that any tumor “treatment” would inhibit the growth of and as such administering the PD1/CTLA4 as per the dosing the dosing regimen above would also be a method of inhibiting tumor growth that reads on all of claims 85-86.
Sumrow does not teach that the PD1/CTLA4 bispecific antibody administered in the method of Sumrow comprises: a) a HC of instant SEQ ID NO: 2 paired with a LC of instant SEQ ID NO: 1 and b) a HC of instant SEQ ID NO: 4 paired with a LC of SEQ ID NO: 3. Sumrow does not teach that the PD1/CTLA4 bispecific antibody comprises an IgG1 Fc having L234F, 235E and P331S substitutions and is formatted as a DuetMab with knob-hole pairing. Sumrow does not teach the patient administered the PD1/CTLA4 bispecific antibodies has a tumor with PDL1 negative. Sumrow does not teach that the anti PD1/CTLA bispecific antibody is administered at a dose of 750 mg.
Kasturirangan teaches a bispecific antibody that binds PD1 and CTLA4 comprising a first heavy chain comprising SEQ ID NO: 9 (same as instant SEQ ID NO: 2) and a first LC comprising SEQ ID NO: 7 (same as instant SEQ ID NO: 1) and also comprising a second HC comprising SEQ ID NO:12 (same as instant SEQ ID NO: 3) and a second LC comprising SEQ ID NO 4 (same as instant SEQ ID NO :4) (Kasturirangan, claim 39), and that this bispecific antibody is administered in methods of treating lung cancer (Kasturirangan, claims 56-57).
Dovedi teaches on the subject of PD1/CTLA4 bispecific antibodies (Dovedi, Abstract). Dovedi teaches that the bispecific antibodies of Dovedi are DuetMab antibodies (which comprise a knob-in-hole linkage) with L234F, L235E and p331S (Dovedi, p 1102, p. 5). Dovedi teaches the bispecific antibodies of Dovedi preferentially binds CDLA4 on PD1 positive T cells versus PD1 negative cells, making the bispecific antibody of Dovedi was engineered to preferentially inhibit PD1 positive on CTLA positive T cells (Dovedi, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to use the specific HC and LC combinations taught by Kasturirangan (HC of instant SEQ ID NO: 2 paired with a LC of instant SEQ ID NO: 1 as well as a HC of instant SEQ ID NO: 3 paired with a LC of instant SEQ ID NO: 4) as the specific sequence the bispecific PD1/CTLA4 antibody of Sumrow. The net result of this combination would be
a bispecific antibody that binds PD1 and CTLA4 comprising a first heavy chain of Kasturirangan’s SEQ ID NO: 9 (same as instant SEQ ID NO: 2) and a first LC of Kasturirangan’s SEQ ID NO: 7 (same as instant SEQ ID NO: 1) and also comprising a second HC of Kasturirangan’s SEQ ID NO:12 (same as instant SEQ ID NO: 3) and a second LC of Kasturirangan’s SEQ ID NO 4 (same as instant SEQ ID NO :4). One of ordinary skill in the art would be motivated to do this in order to form a PD1/CTLA4 bispecific antibody comprising HC and LC sequence pairings known in the art bind PD1 and CTLA4. One of ordinary skill in the art would have a reasonable expectation of success using the HC and LC pairings of Kasturirangan to form the PD1/CTLA4 bispecific antibody of Sumrow because Kasturirangan teaches the HC and LC sequence pairings of Kasturirangan are known in the art to bind PD1 and CTLA4.
It would be prima facie obvious to one of skill in the art to further modify the combined teachings of Sumrow and Kasturiragan to format the CTLA4/PD1 bispecific antibody of Sumrow and Kasturiragan to comprise L234F, 235E and P331S substitutions in a DuetMab format (inherently has a knob-in-hole pairing) of Dovedi and administer the resultant antibody to a PDL1 negative NSCLC patient. One of ordinary skill in the art would be motivated to do this to better treat NSCLC. One of skill in the art would have a reasonable expectation of success formatting the CTLA4/PD1 bispecific antibody of Sumrow and Kasturiragan to comprise L234F, 235E and P331S substitutions in a DuetMab format (inherently has a knob-in-hole pairing) and administer the resultant antibody to a PDL1 negative NSCLC patient because: 1) Dovedi teaches that a PD1/CTLA4 bispecific antibody comprising L234F, 235E and P331S substitutions in a DuetMab format performs far better in PD1 positive patients compared to PDL1 negative patients and 2) one of ordinary skill in the art would reasonably deduce that the lack of PD1’s ligand, PDL1, would lead to a higher proportion of free PD1, allowing the PD1 to behave as normal as its function is not sterically hindered by the binding of its ligand.
It would be prima facie obvious to one of ordinary skill in the art to administer the PD1/CTLA4 bispecific antibody collectively taught by Sumrow, Kasturirangan and Dovedi, said antibody comprising a first heavy chain of Kasturirangan’s SEQ ID NO: 9 (same as instant SEQ ID NO: 2) and a first LC of Kasturirangan’s SEQ ID NO: 7 (same as instant SEQ ID NO: 1) and also comprising a second HC of Kasturirangan’s SEQ ID NO:12 (same as instant SEQ ID NO: 3) and a second LC of Kasturirangan’s SEQ ID NO 4 (same as instant SEQ ID NO :4) and further comprising L234F, 235E and P331S substitutions in a DuetMab format in a method of treating NSCLC, wherein the PD1/CTLA4 antibody is administered at a dose of 750 mg every three weeks in view of the teachings of Sumrow and Kasturirangan. The net result of this application would be a method of treating NSCLC, said method comprising administering the PD1/CTLA4 bispecific antibody collectively taught by Sumrow, Kasturirangan and Dovedi described above at a dose of 750 mg every three weeks.
One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success forming a method of treating NSCLC comprising administering administering the PD1/CTLA4 bispecific antibody collectively taught by Sumrow, Kasturirangan and Dovedi described above at a dose of 750 mg every three weeks because: 1) Kasturirangan teaches administration of a PD1/CTLA4 bispecific antibody in methods of treating lung cancer and 2) Sumrow teaches a method comprising a different bispecific PD1/CTLA4 antibody at a dose between 240 and 800 mg that is administered once every three week as a method of treating NSCLC and starting with a claimed range disclosed in the prior art and arriving at a value within that range via routine experimentation is within the purview of one of skill in the art.
Also, Also, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)
Regarding claims 81 and 85, as evidenced by the instant Specification, administering this particular PD1/CTLA4 bispecific molecule of Kasturirangan in a method of treating NSCLC as taught by Sumrow would naturally expand T cells within a subject with the proportion of newly expanded T cells being about 60%, about, 70 % or about 75% higher compared to the number of T cell clones prior to administration (Specification, ¶ 0062).
Response to Arguments
Applicant's arguments filed 1/30/2026 have been fully considered but they are not persuasive.
Applicant’s makes three arguments with respect to the 35 USC 103 rejection. The first and second argument are interrelated and, as such, they will be addressed together. Applicant argues that the PD1/CTLA4 bispecific antibody of Sumrow is a bispecific tetravalent antibody, while the antibody of the instant Application is a bispecific divalent antibody. Applicant argues that this tetravalent vs bivalent antibody structure affects drug performance and pharmacokinetics. Applicant also argues that the tetravalent vs bivalent nature of the two antibodies coupled with the L234F, 235E and P331S mutations and DuetMab format of the instant claimed antibodies are properties that make using the dosing range of 3-10 mg/mL taught by Sumrow for the divalent PD1/CTLA4 bispecific antibody of the instant claimed invention is not an appropriate dosage range for the tetravalent PD1/CTLA4 bispecific antibody comprising the L234F, 235E and P331S mutations and DuetMab format of Dovedi. Applicant further argues that the Specification demonstrates unexpected effect, such as dose sparing, such as the instant claimed antibody having similar efficacy at a dose of 750 mg Q3W compared to a dose of 1,500 mg, with improved tolerability, citing Figs. 7, 9 and 11 of the Specification. Applicant also argues that the instant claimed antibody produced a favorable progression-free survival compared to pembrolizumab plus chemotherapy.
In response, the dosing effects articulated by Applicant in the preceding paragraph do not constitute results that are unexpected. Figures 7A, 7B, 8A and 8B all show dose escalation data, with Figs. 7A and 7B show T cell activation as a function of dosage and Figs. 8A and 8B showing T cell proliferation as a function of dose. All of these figures are reproduced below:
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In both cases, the relationship between dose and T cell activation or proliferation appears to reach a horizontal asymptote starting at about 225 mg. These results are not unexpected as, in any given cell population, there are a finite number of antigens available for binding. As the proportion of antigen bound to an antibody increases as the concentration of antibody increases, fewer antigen epitopes are available for binding, inevitably leading to the horizontal asymptotes observed in Figs. 7 and 8.
Regarding the “unexpected results” with respect to the favorable progression-free survival compared to pembrolizumab plus chemotherapy, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (See MPEP 716.02(a). In the instant case it is entirely expected that an antibody binding a single tumor-associated antigen (PD1) would not perform as well as another, otherwise similar antibody, that binds PD1 as well as CTLA4 because the antibody has more opportunities for binding upon coming in contact with a cell bearing both of these antigens.
Applicant also argues that administering the instant claimed bispecific antibody to a patient with PDL1-negative NSCLC is nonobvious, given PDL1 NSCLC responds poorly to PDL1 NSCLC, whereas Applicant demonstrates meaningful responses in PDL1 negative patients. As stated above, allegations of nonobvious results must be unexpected in view of the prior art. As stated and articulated above, Dovedi teaches that PD1 positive patients fare better than PD1 negative patients when treated with a PD1/CTLA4 bispecific antibody identical to the antibody of the instant application. As further articulated above, nearly all of the PD1 present in a PDL1 negative patient not bound to its ligand, rendering it accessible to PD1 binding domain of the instant claimed bispecific antibody, whereas a patient expressing high levels of PDL1 would have a higher proportion of their PD1 bound to its PDL1 ligand, rendering the PD1 inaccessible to the PD1-binding domain of the instant claimed antibody, rendering PD1 in that patient “effectively negative”.
Claim(s) 72, 76, 80-81, 85-86 and 91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to 7/27/2020 by way of US 63/057,054, of record) in view of Kasturirangan (Kasturirangan , et al., WO 2017/193032 A2; Published 11/9/2017; Priority to 5/6/2016 by way of US 62/332,788, of record) and Dovedi (Dovedi, et al., Cancer Discov (2021) 11(5):1100) as applied to claims 72, 76, 81, 85-86 above and in further view of Gervais (Gervais, et al, Lung Cancer (2013) 80:185).
The combined teachings of Sumrow, Kasturirangan and Dovedi are discussed above.
The combined teaching s of Sumrow, Kasturirangan and Dovedi do not teach that the PD1/CTLA4 bispecific antibody of Sumrow, Kasturirangan and Dovedi is administered in a method of treating non-squamous NSCLC in conjunction with pemetrexed at 500 mg/m2 and carboplatin at AUC of 5.
Gervias teaches on the subject of combinations of pemetrexed combined with platinum agents for advanced (same as metastatic) NSCLC that is non-squamous (Gervias, Abstract). Gervias teaches that patients were administered 500 mg/m2 pemetrexed and carboplatin at AUC 5 in three-week cycles (Gervias, Abstract). Gervias teaches that combined pemetrexed-carboplatin is a valuble treatment for advanced NSCLC and is restricted to non-squamous NSCLC patients (Gervias, p 189, p. 4-5).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of treating NSCLC taught by Sumrow, Kasturirangan and Dovedi, said method comprising administering the PD1/CTLA4 antibody of Sumrow, Kasturirangan and Dovedi with administration of the pemetrexed/carboplatin of Gervias. The net result of this method would be a method of treating non-squamous NSCLC comprising the combined administration of the PD1/CTLA4 antibody of Sumrow, Kasturirangan and Dovedi at 750 mg with the pemetrexed (500 mg/m2) and carboplatin (AUC 5) of Gervias. One of ordinary skill in the art would have a reasonable expectation of success forming such a method because Gervias teaches that the combination of pemetrexed (500 mg/m2) and carboplatin (AUC 5) is effective for non-squamous NSCLC.
Response to Arguments
Applicant made no arguments specific to this rejection.
Claim(s) 72, 76, 80-81, 85-86 and 92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to 7/27/2020 by way of US 63/057,054, of record) in view of Kasturirangan (Kasturirangan , et al., WO 2017/193032 A2; Published 11/9/2017; Priority to 5/6/2016 by way of US 62/332,788, of record) and Dovedi (Dovedi, et al., Cancer Discov (2021) 11(5):1100) as applied to claims 72, 76, 81, 85-86 above and in further view of Merck, Sharp and Dohme LLC (“MSD”) (MSD, et al., clinical trial NCT02275435; first available 4/10/2019).
The combined teachings of Sumrow, Kasturirangan and Dovedi are discussed above.
The combined teaching s of Sumrow, Kasturirangan and Dovedi do not teach that the PD1/CTLA4 bispecific antibody of Sumrow, Kasturirangan and Dovedi is administered in a method of treating squamous NSCLC in conjunction with paclitaxel at 150-200 mg/m2 and carboplatin at AUC of 6.
MSD teaches on the subject of combinations of carboplatin and paclitaxel for squamous NSCLC (MSD, p1). MSD teaches that patients received paclitaxel at 200 mg/m2 and carboplatin at AUC 6, both on a 3-week cycle (MSD, p 6).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of treating NSCLC taught by Sumrow, Kasturirangan and Dovedi, said method comprising administering the PD1/CTLA4 antibody of Sumrow, Kasturirangan and Dovedi with administration of the paclitaxel/carboplatin of MSD. The net result of this method would be a method of treating squamous NSCLC comprising the combined administration of the PD1/CTLA4 antibody of Sumrow, Kasturirangan and Dovedi at 750 mg with the paclitaxel (200 mg/m2) and carboplatin (AUC 6) of MSD). One of ordinary skill in the art would have a reasonable expectation of success forming such a method because MSD teaches that the combination of paclitaxel and carboplatin was known well enough in the art as a treatment for squamous NSCLC to justify an in-human clinical trials.
Response to Arguments
Applicant made no arguments specific to this rejection.
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 72, 81 and 85-86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,457,732 and claims 1-43 of U.S. Patent No. RE49908 both in view of in view of Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to 7/27/2020 by way of US 63/057,054, of record) and Dovedi (Dovedi, et al., Cancer Discov (2021) 11(5):1100)
The patented claims are directed to a bispecific antibody that binds PD1 and CTLA4 comprising a first heavy chain of patented SEQ ID NO: 9 (same as instant SEQ ID NO: 2) and a first LC of patented SEQ ID NO: 7 (same as instant SEQ ID NO: 1) and also comprising a second HC of patented SEQ ID NO:12 (same as instant SEQ ID NO: 3) and a second LC of patented SEQ ID NO: 4 (same as instant SEQ ID NO :4) as well as administering these bispecific antibodies in methods of treating NSCLC. Regarding claims 81 and 85, as evidenced by the instant Specification, administering this particular PD1/CTLA4 bispecific molecule in a method of treating NSCLC as taught by the reference patents would inherently expand T cells within a subject with the proportion of newly expanded T cells being about 60%, about, 70 % or about 75% higher compared to the number of T cell clones prior to administration (Specification, ¶ 0062).
The reference patent does not teach that the bispecific PD1/CTLA4 antibody of the reference patents is administered in methods of treating/inhibiting the growth of NSCLC, said methods comprising administering the PD1/CTLA4 antibody of the reference patents at 750 mg once every three weeks, wherein the subject is a human. reference patent does not teach that the PD1/CTLA4 bispecific antibody comprises an IgG1 Fc having L234F, 235E and P331S substitutions and is formatted as a DuetMab with knob-hole pairing. reference patent does not teach the patient administered the PD1/CTLA4 bispecific antibodies has a tumor with PDL1 negative
Sumrow teaches on dosing regimens for administering a PD-1xCTLA-4 bispecific molecules (Sumrow, Abstract). Sumrow teaches a method of treating cancer, said method comprising a PD1/CTLA4 bispecific binding molecule administered once every three weeks (Sumrow, claim 1), wherein the dose of the bispecific molecule administered at 3-10 mg/kg (Sumrow, claim 15), wherein the cancer is NSCLC (Sumrow, Claim 25). Please note that, for an average 80 kg human, 3-10 mg/kg is the same as 240-800 mg mg (6 mg/kg * 80 kg = 480 mg). Sumrow teaches that the PD1/CTLA4 bispecific binding molecule of Sumrow is administered in conjunction with chemotherapeutic agents (Sumrow, ¶ 152).
Dovedi teaches on the subject of PD1/CTLA4 bispecific antibodies (Dovedi, Abstract). Dovedi teaches that the bispecific antibodies of Dovedi are DuetMab antibodies (which comprise a knob-in-hole linkage) with L234F, L235E and p331S (Dovedi, p 1102, p. 5). Dovedi teaches the bispecific antibodies of Dovedi preferentially binds CDLA4 on PD1 positive T cells versus PD1 negative cells, making the bispecific antibody of Dovedi was engineered to preferentially inhibit PD1 positive on CTLA positive T cells (Dovedi, Abstract).
It would be prima facie obvious to one of skill in the art to modify the PD1/CTLA4 bispecific antibody of the reference patent to comprise L234F, 235E and P331S substitutions in a DuetMab format (inherently has a knob-in-hole pairing) of Dovedi and administer the resultant antibody to a PDL1 negative NSCLC patient. One of ordinary skill in the art would be motivated to do this to better treat NSCLC. One of skill in the art would have a reasonable expectation of success formatting the CTLA4/PD1 bispecific antibody of the reference patent to comprise L234F, 235E and P331S substitutions in a DuetMab format (inherently has a knob-in-hole pairing) and administer the resultant antibody to a PDL1 negative NSCLC patient because: 1) Dovedi teaches that a PD1/CTLA4 bispecific antibody comprising L234F, 235E and P331S substitutions in a DuetMab format performs far better in PD1 positive patients compared to PDL1 negative patients and 2) one of ordinary skill in the art would reasonably deduce that the lack of PD1’s ligand, PDL1, would lead to a higher proportion of free PD1, allowing the PD1 to behave as normal as its function is not sterically hindered by the binding of its ligand.
It would be prima facie obvious to one of ordinary skill in the art to administer bispecific PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi, said antibody comprising a first heavy chain of patented SEQ ID NO: 9 (same as instant SEQ ID NO: 2) and a first LC of patented SEQ ID NO: 7 (same as instant SEQ ID NO: 1) and also comprising a second HC of patented SEQ ID NO:12 (same as instant SEQ ID NO: 3) and a second LC of patented SEQ ID NO: 4 (same as instant SEQ ID NO :4) and further comprising L234F, 235E and P331S substitutions in a DuetMab format at Sumrow’s dose of 750 mg. The net result of this combination would be a method of treating NSCLC comprising administering the bispecific PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi described above at a dose of 750 mg that is administered once every three weeks to a human patient in need thereof. One of ordinary skill in the art would be motivated to do this in order to better treat NSCLC. One of ordinary skill in the art would have a reasonable expectation of success administering the bispecific PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi and discussed above at a dose of 750 mg administered once every three weeks because 1) Sumrow teaches doses from 3-10 mg/kg administered every 3 weeks as appropriate dosage/interval schemes for the treatment of NSCLC with a bispecific PD1/CTLA4 antibody and 2) it is within the purview of one of skill in the art to start with numerical ranges disclosed in the prior art and arrive at an optimal number via routine experimentation.
Also, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)
Regarding claim 86, the method of treating an NSCLC tumor comprising administering the PD-1xCTLA-4 bispecific molecules would also be a method of inhibiting growth of an NSCLC tumor because cancer is an uncontrolled growth of tumor cells that any tumor “treatment” would inhibit the growth of and as such administering the PD1/CTLA4 as per the dosing the dosing regimen above would also be a method of inhibiting tumor growth that reads on all of claims 86.
Response to Arguments
Applicant made no arguments specific to this rejection.
Claims 72, 76, 80-81, 85-86 and 92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,457,732 and claims 1-43 of U.S. Patent No. RE49908 both in view of in view of Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to7/27/2020 by way of US 63/057,054, of record) and Dovedi (Dovedi, et al., Cancer Discov(2021)11(5):1100) as applied to claims 72, 81 and 85-86
above and in further view of view of Merck, Sharp and Dohme LLC (“MSD”) (MSD, et al., clinical trial NCT02275435; first available 4/10/2019).
The combined teachings of the reference patent Sumrow, and Dovedi are discussed above.
The combined teaching s of the reference patent Sumrow, and Dovedi do not teach that the PD1/CTLA4 bispecific antibody of the reference patent Sumrow, and Dovedi is administered in a method of treating squamous NSCLC in conjunction with paclitaxel at 150-200 mg/m2 and carboplatin at AUC of 6.
MSD teaches on the subject of combinations on carboplatin and paclitaxel for squamous NSCLC (MSD, p1). MSD teaches that patients received paclitaxel at 200 mg/m2 and carboplatin at AUC 6, both on a 3-week cycle (MSD, p 6).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of treating NSCLC collectively taught by the reference patent, Sumrow, and Dovedi, said method comprising administering the PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi and discussed above with administration of the paclitaxel/carboplatin of MSD. The net result of this method would be a method of treating squamous NSCLC comprising the administration of the PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi and discussed above at the 750 mg dose of Sumrow in combination with the paclitaxel (200 mg/m2) and carboplatin (AUC 6) of MSD). One of ordinary skill in the art would have a reasonable expectation of success forming such a method because MSD teaches that the combination of paclitaxel and carboplatin was known well enough in the art as a treatment for squamous NSCLC to justify an in-human clinical trials.
Response to Arguments
Applicant made no arguments specific to this rejection.
Claim(s) 72, 76, 80-81, 85-86 and 91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sumrow (Sumrow, et al., US20230312767 A1; Published 10/5/2023; priority to 7/27/2020 by way of US 63/057,054, of record) in view of Kasturirangan (Kasturirangan , et al., WO 2017/193032 A2; Published 11/9/2017; Priority to 5/6/2016 by way of US 62/332,788, of record) and Dovedi (Dovedi, et al., Cancer Discov (2021) 11(5):1100) as applied to claims 72, 81, 85-86 above and in further view of Gervais (Gervais, et al, Lung Cancer (2013) 80:185).
The combined teachings of the reference patent, Sumrow, and Dovedi are discussed above.
The combined teaching s of the reference patent, Sumrow, and Dovedi do not teach that the PD1/CTLA4 bispecific antibody collectively taught by the reference patent and Dovedi and described above is administered in a method of treating non-squamous NSCLC in conjunction with pemetrexed at 500 mg/m2 and carboplatin at AUC of 5.
Gervias teaches on the subject of combinations of pemetrexed combined with platinum agents for advanced (same as metastatic) NSCLC that is non-squamous (Gervias, Abstract). Gervias teaches that patients were administered 500 mg/m2 pemetrexed and carboplatin at AUC 5 in three-week cycles (Gervias, Abstract). Gervias teaches that combined pemetrexed-carboplatin is a valuable treatment for advanced NSCLC and is restricted to non-squamous NSCLC patients (Gervias, p 189, p. 4-5).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of treating NSCLC collectively taught by the reference patent, Sumrow, and Dovedi, said method comprising administering the PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi and discussed above with administration of the pemetrexed/carboplatin of Gervias. The net result of this method would be a method of treating non-squamous NSCLC comprising the administration of the PD1/CTLA4 antibody collectively taught by the reference patent and Dovedi and discussed above at the 750 mg dose of Sumrow in combination with the pemetrexed (500 mg/m2) and carboplatin (AUC 5) of Gervias. One of ordinary skill in the art would have a reasonable expectation of success forming such a method because Gervias teaches that the combination of pemetrexed (500 mg/m2) and carboplatin (AUC 5) is effective for non-squamous NSCLC.
Response to Arguments
Applicant made no arguments specific to this rejection.
Conclusion
Claims 72,76,80-81,85-86 and 91-92 are rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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