DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1-3, 6-15, 17-28, 31 and 32 are pending.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §119 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 18/590121, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application.
Particularly, claim 3 and 21-28 are not supported by the prior-filed application because the limitation, “wherein the effective amount of the anti-PD-L 1 antibody is about 1200 mg” is not supported in the prior-filed application US Patent Application NO. 18590121). It has been determined that the dosages of about 2 mg/kg, 4 mg/kg, 8 mg/kg, 15 mg/kg, or 30 mg/kg in 21-day cycles recited in the previous priority documents are not equivalent to the fixed dosage of 1200 mg in the IDS references cited by Applicant as demonstrating unexpected results. Thus, claims 3 and 21-28 are hereby assigned the priority date of October 31, 2024, the filing date of the present application.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter, “wherein the effective amount of the anti-PD-L1 antibody is about 1200 mg. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o).
Applicant states that the specification of provisional U.S. Patent Application No. 61/802,296 ("the Priority Application"), to which the instant application claims priority benefit, discloses that the anti-PD-L 1 antibody recited in the present claims may be administered at a dose of 15 mg/kg in 21-day cycles (see, e.g. [000292] of the Priority Application and [000291] of the present application). Applicant argues that a skilled artisan would have recognized, at the time of the filing of the Priority Application, that a 15 mg/kg weight-based dose can be converted to a flat dose of 1200 mg based on an
average patient body weight of about 80 kg, which is an accepted standard of the average patient weight for the purpose of drug dosing calculations. ApplciantA standard average patient body weight of 80 kg, e.g., for calculating weight-based dosing, was already well established in the art before the priority date of the present application. For instance, several publications discussed below describe utilizing 80 kg as a standard body weight for patients when calculating doses of various therapeutic agents. Applicant argues that as evidenced by the foregoing publications, an average patient body weight of 80 kg, e.g., for calculating weight-based dosing, was an accepted standard in the art prior to the priority date of the present application. Applicant argues that an 80-kg patient being administered atezolizumab according to a weight-based dosing of 15 mg/kg should be administered a dose of 1200 mg. Therefore, contrary to the Office's
allegations, the present application provides written description support for the claimed subject matter of administering the presently recited anti-PD-L 1 antibody at a dose of about 1200 mg. Applicant argue that they were was plainly in possession of the claimed subject matter.
Applicant’s argument has been considered but are not persuasive. Applicant is trying to equate a fixed dosage, as disclosed by the after-filing references, with the specification’s disclosure of variable dosages which depend on the weight of the subject being treated. The specification does not disclose nor do the claims recite that an 80 kg male patient is being treated. Boxenbaum states “assume a representative 80 kg patient” for calculating a maintenance dosage of a drug. Shore assumes a conservative estimate of 80 Kg for patient. Kissela also uses a hypothetical 80 kg patient for looking at the cost effectiveness of a treatment. The references do not disclose that this is an average weight for patients nor that this is the standard weight to be used for all calculations for dosage regimens. Without starting at a hypothetical weight of 80 kg, a person of skill in the art would not be able to convert the specification’s disclosure of variable dosages of about 2 mg/kg, 4 mg/kg, 8 mg/kg, 15 mg/kg, or 30 mg/kg into a fixed dosage of 1200 mg. One of skill in the art looking at the specification would not be able to deduce a fixed dosage of 1200 mg from the specification’s disclosure of variable dosages of about 2 mg/kg, 4 mg/kg, 8 mg/kg, 15 mg/kg, or 30 mg/kg. These variable dosages disclosed in the specification are not equivalent to the fixed dosage of 1200 mg in the IDS references cited by Applicant as demonstrating unexpected results.
35 USC § 102 rejection maintained
The rejections of claim(s) 3, 21, 25 and 28 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Fehrenbacher et al (Lancet 387: 1837-1846, 2016, IDS) are maintained.
The claims are drawn to a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody, wherein the effective amount of the anti-PD-L1 antibody is about 1200 mg.
Fehrenbacher disclose the treatment of patients with previously treated NSCLC with 1200 mg of atezolizumab intravenously every three weeks for 36 weeks (page 1838, 1st column to 1839, 1st column). Fehrenbacher disclose that treatment response was associated with PD-L1 expression (Id).
The rejections of claim(s) 3, 21, 25 and 28 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Rittmeyer et al (Lancet 389: 255-265, 2017, IDS) are maintained.
Rittmeyer disclose the treatment of previously treated patients with NSCLC with 1200 mg atezolizumab every three weeks for 36 weeks (2nd and 3rd pages, Methods). Rittmeyer discloses measuring PD-L1 expression on tumor cells or tumour-infiltrating immune cells (5th page Outcomes; Statistical analysis).
The rejections of claim(s) 3 and 21-28 under pre-AIA 35 U.S.C. 102(b) as being anticipated by West et al (Lancet Oncol 20:924-937, 2019, IDS) are maintained.
The claims are drawn to a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody, wherein the effective amount of the anti-PD-L1 antibody is about 1200 mg, combination with an effective amount of carboplatin, etoposide, paclitaxel, nab-paclitaxel or cisplatin.
West disclose the treatment of patients with stage IV non-squamous non-small-cell lung cancer with 1200 mg intravenously every 3 weeks in combination with carboplatin (area under the curve 6 mg/mL per min every 3 weeks) plus nabpaclitaxel
(100 mg/m2 intravenously every week) for four or six cycles (page 926, 1st column, 3rd paragraph; page 926, 2nd column, 5th paragraph). West disclose measuring expression of PD-L1 on tumor cells and tumor infiltrating cells by immunohistochemistry (page 926, 2nd column, 4th paragraph; page 927, 2nd column, 4th paragraph).
The rejections of claim(s) 3 and 21-28 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Felip et al (the Lancet 398:1344-1357, 2019, IDS) are maintained.
Felip disclose the treatment of patients with completely resected stage IB to IIIA NSCLC with 1200 mg atezolizumab intravenously every 21 days for 16 cycles or 1 year after 75 mg/m2 cisplatin chemotherapy intravenously for up to four 21 days cycles (page 1346). Felip disclose that patients had greater than 1% of tumor cells expressing PD-L1 (Id).
Applicant argues that the Priority Application provides written description for the feature specifying that an effective amount of the anti-PD-L 1 antibody is about 1200 mg. Applicant contrary to the Office's conclusions, claims 3 and 21-28, which recite said subject matter or incorporate said subject matter by reference, are entitled to a priority date of March 15, 2013. Applicant argues that none of Fehrenbacher, Rittmeyer,
West, and Felip qualifies as prior art
In response as discussed above, the specification in the previous priority documents discloses variable dosages of about 2 mg/kg, 4 mg/kg, 8 mg/kg, 15 mg/kg, or 30 mg/kg in 21-day cycles. These variable dosages are not equivalent to the fixed dosage of 1200 mg in the IDS references cited by Applicant as demonstrating unexpected results. Thus, claims 3 and 21-28 are hereby assigned the priority date of October 31, 2024, the filing date of the present application.
35 USC § 103 rejection maintained
The rejections of claims 1-2, 6-10, 12-15, 17, 18, 20, 31 and new claim 32 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Irving et al (US 2010/0203056, published August 12, 2010, IDS) in view of Korman et al (US 2009/0055944, published February 26, 2009) and Cogswell et al (US 2013/0309250, published November 21, 2013, effective filing date May 15, 2012, IDS) are maintained.
The claims are drawn to a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 15);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 16);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 17);
(e) an HVR-L2 sequence of SASFL YS (SEQ ID NO: 18); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 19).
Irving teaches treating lung cancer with anti-PD-L1 antibody comprising the listed CDRs (paragraphs 40; see sequence comparison below). Irving discloses the chemotherapeutic agents, carboplatin, cisplatin and paclitaxel (paragraphs 40, 228, 230). Cogswell discloses an association between pretreatment tumor PD-L1 expression and response to (paragraph 22; Figure 8).
Irving does not specifically disclose the treatment of non-small cell lung cancer comprising administering an effective amount of an anti-PD-L 1 antibody every three weeks.
Korman teaches the treatment of lung cancer comprising administering a dosage of 0.001 to 100 mg/kg of an anti-PD-L 1 antibody every three weeks (paragraph 519, 534).
Cogswell teaches the treatment of non-small cell lung cancer comprising administering 10mg/kg (900 mg for a 90 kg male) of an anti-PD-L1 antibody (paragraphs 6, 12, 24, 27, 213, 214, 262). Cogswell disclose the anti-PD-L1 antibody BMS-936559 was used to treat non-small cell lung cancer (paragraphs 255-262). Cogwell disclose the use of carboplatin in the treatment of non-small cell lung cancer (paragraph 215).
Cogswell further disclose measuring levels of PD-L1 on tumor infiltrating lymphocytes to determine responsiveness to anti-PD-1 antibodies (paragraphs 5, 22, 28, 46, 95; Fig 8A) . Cogswell discloses that there was a significant correlation of tumor cell surface PD-L1 expression with objective clinical response (paragraphs 22, 28, 95; Figure 8). Given that anti-PD-1 antibodies and anti-PD-L1 antibodies both block the PD-1-PD-L1 binding, it would have been obvious to use the PD-L1 expression on tumor infiltrating lymphocytes and tumor cells to determine responsiveness to anti-PD-L1 antibodies (paragraphs 9-12, 46, 56). Measuring PD-L1 in tumor tissue would measure the expression of PD-L1 on tumor cells.
With regards to the limitation “presence of a detectable expression level of PD-L1 protein in tumor infiltrating immune cells covering > 10% of tumor area in a tumor tissue sample obtained from the individual” and “wherein prior to administration of the treatment to the individual, a tumor tissue sample obtained from the individual is determined to have a detectable expression level of PD-L1 protein in tumor cells covering > 1 % of tumor area in the tumor tissue sample obtained from the individual” Cogswell discloses that there was a significant correlation of tumor cell surface PD-L1 expression with objective clinical response. Thus, it would have been obvious to measure tumor PD-L1 levels prior to treatment with the anti-PD-L1 antibody. Furthermore, the detectable expression of the PD-L1 protein in tumor infiltrating immune cells is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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). Thus, absent unexpected results it would have been obvious to measure tumor tissue and tumor infiltrating immune cell expression of PD-L1 prior to treatment with anti-PD-L1 antibodies and correlate expression of PD-L1 with clinical response.
One of ordinary skill in the art would have been motivated to combine Irving, Korman and Cogswell because they all teach the treatment of lung cancer with anti-PD-L1 antibodies. Non-small cell lung cancer is the most common type of lung cancer. It would have been prima facie obvious to combine the teachings of Irving, Korman and Cogswell to have a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 15);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 16);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 17);
(e) an HVR-L2 sequence of SASFL YS (SEQ ID NO: 18); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 19).
Applicant argues that the presently claimed methods are based, at least in part, on Applicant's discovery that administering the anti-PD-L 1 antibody MPDL3280A on a three-week dosing interval is effective for treating numerous types of cancer, including NSCLC. Applicant argues that the efficacy of this treatment is demonstrated in the Examples of the specification as filed, which describe the experimental methods and results of a phase I multicenter clinical study (corresponding to Clinical Trial Identifier NCT01375842; as evidenced by "A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL 1] Antibody) to Evaluate Safety, Tolerability, and Pharmacokinetics in Participants with Locally Advanced or Metastatic Solid Tumors," in which more than 250 patients having various forms of cancer, including NSCLC, were treated by administering MPDL3280A, e.g., with a dosing interval of one dose every three weeks. Example 2 of the specification as filed describes the results of the study, which corresponds to Clinical Trial NCT01375842, in which treatment with MPDL3280A administered every three weeks was continued until progression of disease or unacceptable activity.
Applicant’s arguments have been considered but are not persuasive. In response it is noted that the examples are primarily concerned with the correlation between elevated PD-L1 gene expression in tumor samples and the patients' clinical response to anti-PD-L1. The results in Example 2 do not show the comparative efficacy of the treatment nor the safety of a specific therapeutic regimen but discloses that there appears to be a correlation between elevated PD-L1 gene expression in tumor samples and the patients' clinical response to anti-PD-L1.
Further, Example 2 discloses that the tumor types enrolled specifically included
NSCLC (squamous and non-squamous histology), melanoma, RCC, CRC, gastric cancer, breast cancer, SCCHN, pancreatic cancer, bladder cancer and hematologic malignancies. Thus, it is not clear what results are associated with NSCLC.
Applicant argues that the surprising efficacy of the presently claimed methods is demonstrated in post-filing clinical data described in each of Fehrenbacher, Rittmeyer, West, and Felip, the teachings of which were detailed in the previously filed response dated August 19, 2025, to the non-final Office Action of May 19, 2025 ("the Previous Response").
In addition, Applicant argues that the cited references fail to teach or suggest the presently claimed methods. Applicant argues that Irving discloses anti-PD-L 1 antibodies for the treatment of T cell dysfunctional disorders, which include acute infections, chronic infections, and tumor immunity. Applicant argues that the cited references fail to teach or suggest the presently claimed methods. Applicant argues that Korman discloses nine anti-PD-L1 antibodies but nowhere does Korman teach or suggest the anti-PD-L1 antibody of the present claims. Applicant argues that Korman merely describes that a dosing interval for an antibody can vary widely, ranging from once a week to as infrequently as once every three to six months. [0519] of Korman provides a list of exemplary cancers for treatment, which exceeds forty different types of cancer and does not recite NSCLC. Applicant argues that Korman additionally discloses that dosing intervals of the anti-PD-L1 antibody may vary within a single dosing regimen for any of the anti-PD-L 1 antibodies described therein. This broad range of dosing regimens does not provide any guidance that would have led a skilled artisan to specifically select, from this extensive range of dosing intervals and types of cancer, a particular dosing interval of three weeks for treating NSCLC. regarding this large range and high number of possible combinations in an obvious to try analysis. Applicant states that M.P.E.P. § 2144.05 states "if the reference's disclosed range is so broad as to encompass a very large number of possible distinct compositions, this might present a situation analogous to the obviousness of a species when the prior art broadly discloses a genus," Applicant argues that based on Korman, a skilled artisan would have had no motivation to specifically select a dose interval of three weeks for treating NSCLC with the presently claimed anti-PD-L1 antibody. Applicant argues that Korman discloses administration of an anti-PD-L1 antibody at a dose amount spanning six orders of magnitude. Applicant argues that a broad range of doses described in Korman would not have provided any motivation for a skilled artisan to arrive at the doses of about 15 mg/kg, about 20 mg/kg, or about 30 mg/kg, as recited in present claim 2, or at the pinpoint dose of about 1200 mg, as recited in present claim 3.
Applicant argues that Cogswell discloses treating an infection or cancer in an individual via administration of an anti-PD-1 antibody (e.g., BMS-936558) or an anti-PD-L 1 antibody (e.g., BMS-936559). Applicant argues that Korman, is silent
with respect to the presently recited anti-PD-L 1 antibody and does not describe any working in which an anti-PD-L 1 antibody is administered to a patient with NSCLC Applicant argues that Korman describes a list of over forty exemplary cancers for treatment, in which NSCLC is not included. Applicant further argues that Korman merely describes a wide range of prophetic dosing intervals, ranging from once a week to
as infrequently as once every six months. Applicant argues that even assuming a skilled artisan would have been motivated to combine the teachings of Irving and Korman, which Applicant does not concede, a skilled artisan would have had no motivation to treat a patient with NSCLC at a specific dosing frequency of every three weeks.
Applicant’s arguments have been considered but are not persuasive. In response to Applicant's arguments against the Irving, Korman, and Cogswell individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed above there is ample motivation to combine the references.
In addition, the specification discloses that one typical daily dosage might range from about 1 μg/kg to 100 mg/kg (paragraph 290). It is noted that the specification does not specifically recite the claimed fixed dosage of 1200 mg. The specification discloses that for repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs (Id). Such doses may be administered intermittently, e.g., every week or every three weeks (Id). Thus, the specification discloses a wide range of therapeutic regimens that may be used to administer the anti-PD L1 antibody. As discussed above, the art discloses the specific anti-PD-L1 antibody claimed as well as ranges which encompass the claimed therapeutic regimens.
As previously disclosed, optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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). Thus, absent unexpected results, as discussed above, it would have been prima facie obvious to combine the teachings of Irving, Korman and Cogswell to have a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 15);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 16);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 17);
(e) an HVR-L2 sequence of SASFL YS (SEQ ID NO: 18); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 19).
In response to Applicant argues that the surprising efficacy of the presently claimed methods is demonstrated in post-filing clinical data described in each of Fehrenbacher, Rittmeyer, West, and Felip, Rittmeyer discloses that pembrolizumab compared with docetaxel has shown a median overall survival of 10·4 months versus 8·5 months (HR 0·71, 95% CI 0·58–0·88) at the approved dose of 2 mg/kg in a patient population with non-small-cell lung cancer who expressed PD-L1 in 1% or more of tumour cells (page 3, 2nd paragraph). Thus, it is not clear if the post-filing clinical data were unexpected or were only comparable to the results obtained with other checkpoint inhibitors. It is also not clear if the administration dosage of 1200 mg every three weeks was superior to other therapeutic regimens of the claimed anti-PD-L1 antibody.
In response to Applicant argument that the presently claimed methods are based on Applicant's discovery that administering the anti-PD-L 1 antibody MPDL3280A on a three-week dosing interval is effective for treating numerous types of cancer, as discussed below, the exact dosage administered every three weeks would be a critical factor in the analysis for unexpected results. Applicant has not specifically demonstrated that administering the anti-PD-L 1 antibody MPDL3280A on a three-week dosing interval for any dosage regimen would be effective.
In response to Applicant’s argument that like Korman, Cogswell is silent
with respect to the presently recited anti-PD-L1 antibody, both Korman and Cogswell disclose the treatment of lung cancer with anti-PD-L1 antibodies while Irving teaches treating lung cancer with the claimed anti-PD-L1 antibody. As discussed previously it would have been obvious to substitute Irving’s anti-PD-L1 antibodies for the anti-PD-L1 antibodies of Korman and Cogswell
In response, to Applicant’s argument that Cogswell is the only reference that provides working examples of treating NSCLC, a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. Korman teaches the treatment of lung cancer comprising administering a dosage of 0.001 to 100 mg/kg of an anti-PD-L 1 antibody every three weeks (paragraph 519, 534). Irving teaches treating lung cancer with anti-PD-L1 antibody comprising the listed CDRs (paragraphs 40; see sequence comparison below). It is noted that approximately 85% of lung cancers are NSCLC. Thus, the methods of both Korman and Irving encompasses the treatment of NSCLC.
The rejections of claims 1-3, 6-15, 17, 18, 20, 31 and new claim 32 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Irving et al (US 2010/0203056, published August 12, 2010, IDS) in view of Korman et al (US 2009/0055944, published February 26, 2009, cited previously) and Cogswell et al (US 2013/0309250, published November 21, 2013, effective filing date May 15, 2012, IDS) in further view of Zitvogel and Kroemer (Oncoimmunol 1:1223-1225, 2012) are maintained.
Neither Irving, Korman nor Cogswell disclose the anti-PD-L1 antibody MPDL3280A.
Zitvogel disclose that MPDL3280A is one of six agents that block the PD-1/PD-L1 pathway in clinical studies (page 1224, 2nd column, 2nd paragraph). Zitvogel also disclose the anti-PD-L1 antibody, BMS-936559 (Id). Zitvogel disclose that anti-PD-L1 antibodies may be used to treat lung cancer (page 1223, 1st column 1st paragraph).
One of ordinary skill in the art would have been motivated to apply Zitvogel’s anti-PD-L1 antibody MPDL3280A because Irving, Korman, Cogswell and Zitvogel all disclose the treatment of lung cancer with anti-PD-L1 antibodies. It would have been prima facie obvious to substitute Zitvogel’s anti-PD-L1 antibody MPDL3280A for Cogswell’s BMS-936559 because Zitvogel discloses that both MPDL3280A and BMS-936559 are in clinical trials for the treatment of cancer.
Applicant argues that Zitvogel cannot remedy the deficiencies of Irving, Korman, and Cogswell because Zitvogel fails to teach or suggest the required features of claim 1 because Zitvogel merely reiterates the teachings of Cogswell and simply mentions that MPDL3280A is one of six PD-1/PD-L 1 blocking agents under clinical evaluation.
In response, as discussed above, Irving, Korman, and Cogswell teach a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of the anti-PD-L1 antibody, MPDL3280A every three weeks
The rejections of claim 1-3, 6-10, 12-15, 17, 18-20, 31 and new claim 32 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Irving et al (US 2010/0203056, published August 12, 2010, IDS) in view of Korman et al (US 2009/0055944, published February 26, 2009, cited previously) and Cogswell et al (US 2013/0309250, published November 21, 2013, effective filing date May 15, 2012, IDS) in further view of Gerdes et al (US 2013/0195854, published August 1, 2013, filed January 29, 2013 are maintained.
Neither Irving, Korman nor Cogswell disclose the that the IHC is performed using the Ventana Benchmark XT. (paragraph 110).
Gerdes disclose that IHC for determining drug responsiveness was performed on the Ventana Benchmark XT (paragraphs 8, 9, 110).
One of ordinary skill in the art would have been motivated to apply Gerdes’s Ventana Benchmark XT for performing IHC because both Cogswell and Gerdes discloses performing automated IHC on markers used for determining drug responsiveness. It would have been prima facie obvious to substitute Gerdes’s Ventana Benchmark XT for the automated IHC of Cogswell because both Gerdes and Cogswell were performing IHC for the purpose of determining drug responsiveness.
Applicant argue that Gerdes fails to remedy the deficiencies of Irving, Korman, and Cogswell. Applicant argues that Gerdes is silent with respect to anti-PD-L 1 antibodies and simply does not teach or suggest methods of treatment using the anti-PD- L1 antibody of the present claims. Applicant argues that Gerdes teaches using the Ventana Benchmark XT platform for determining the level of tumor infiltration by NKp46+ cells. Applicant argues that nowhere does Gerdes teach or suggest administering an anti-PD-L 1 antibody to an individual that has NSCLC, let alone administering the specified anti-PD-L 1 antibody to the individual every three weeks.
For the reasons set forth above and the reasons of record, the rejections are maintained.
In addition, Applicant’s argue as evidenced by the post-filing data detailed in the previous response (i.e., the data described in each of Fehrenbacher, Rittmeyer, West, and Felip, each of which demonstrate the efficacy of atezolizumab when administered to a patient with NSCLC every three weeks), the presently claimed methods, which
comprise administration of an effective amount of the recited anti-PD-L 1 antibody (e.g., MPDL3280A (atezolizumab)) at a specific dosing frequency of every three weeks, exhibited surprisingly high efficacy in treating individuals with NSCLC.
Applicant’s arguments have been considered but are not persuasive. MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
The references cited by Applicant, Fehrenbacher, Rittmeyer, West and Felip, all disclose a therapeutic regimen comprising a fixed dose of 1200 mg atezolizumab (MPDL3280A) intravenously every three weeks for up to 16 cycles. The present claims disclose administering an effective amount of the anti-PD-L 1 antibody every three weeks, wherein the effective amount of the anti-PD-L 1 antibody is about 15 mg/kg, about 20 mg/kg, or about 30 mg/kg. Thus, the rejected claims are not commensurate in scope with the references that Applicant cites as exemplary of unexpected results. The exact dosage administered every three weeks would be a critical factor in the analysis for unexpected results.
Double Patenting rejections maintained
The rejections of claims 1-3, 6-15, 17-20 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 and 36-38 of U.S. Patent No. 8,217,149 in view of in view of Korman et al (US 2009/0055944, published February 26, 2009, cited previously) and Cogswell et al (US 2013/0309250, published November 21, 2013, effective filing date May 15, 2012, IDS) in further view of Zitvogel and Kroemer (Oncoimmunol 1:1223-1225, 2012, cited previously) are maintained.
The claims are drawn to a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 15);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 16);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 17);
(e) an HVR-L2 sequence of SASFL YS (SEQ ID NO: 18); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 19).
The claims of US 8,217,149 are drawn to an isolated heavy chain variable region polypeptide that specifically binds to PD-L1 comprising an HVR-H1, HVRH2 and HVR-H3 sequence, wherein the HVR-H1 sequence is GFTFSX1SWIH, the HVR-H2 sequence is AWIX2PYGGSX3YYADSVKG and the HVR-H3 sequence is RHWPGGFDY. The identical CDRs as disclosed in the present application. The specification of US 8,217,149 discloses that the anti-PD-L1 antibody may be used to treat lung cancer (column 10, lines 5-9).
Korman teaches the treatment of lung cancer comprising administering a dosage of 0.001 to 100 mg/kg of an anti-PD-L 1 antibody every three weeks (paragraph 519, 534).
Cogswell teaches the treatment of non-small cell lung cancer comprising administering 10mg/kg (900 mg for a 90 kg male) of an anti-PD-L1 antibody (paragraphs 6, 12, 24, 27, 213, 214, 262). Cogswell disclose the anti-PD-L1 antibody BMS-936559 was used to treat non-small cell lung cancer (paragraphs 255-262). Cogwell disclose the use of carboplatin in the treatment of non-small cell lung cancer (paragraph 215).
Zitvogel disclose that MPDL3280A is one of six agents that block the PD-1/PD-L1 pathway in clinical studies (page 1224, 2nd column, 2nd paragraph). Zitvogel also disclose the anti-PD-L1 antibody, BMS-936559 (Id). Zitvogel disclose that anti-PD-L1 antibodies may be used to treat lung cancer (page 1223, 1st column 1st paragraph).
Applicant argues that the scope of claims 1- 27 and 36-38 of the '149 Patent and the scope of the present claims are entirely different and therefore patentably distinct.
Applicant argues that the specification of the '149 Patent is silent with respect to treating NSCLC and administering the presently claimed anti-PD-L 1 antibody every three weeks, which are essential features of the claimed methods.
Applicant argues as above in response to the 35 U.S.C. § 103(a) rejection regarding the deficiencies of Korman, Cogswell, and Zitvogel also apply, mutatis mutandis, to this nonstatutory double patenting rejection.
Applicant’s arguments have been considered but are not persuasive. The claims of claims of US 8,217,149 are drawn to the claimed anti-PD-L1 antibody. Korman and Cogswell disclose therapeutic regimens that overlap with the claimed therapeutic regimens. As previously discussed, Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention. One of ordinary skill in the art would have been motivated to combine Korman and Cogswell with US 8,217,149 because they all disclose the treatment of lung cancer with anti-PD-L1 antibodies.
Therefore, claims 1-3, 6-15, 17-20 and 31 of the instant application are not patentably distinct since U.S. Patent No. 8,217,149 claimed the same product, the presently claimed anti-PD-L1 antibody, and discloses a method of treating lung cancer with the anti-PD-L1 antibody in the specification.
The rejections of claims 1-3, 6-15, 17-28 and 31 on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10,570,213 in view of in view of in view of Zitvogel and Kroemer (Oncoimmunol 1:1223-1225, 2012, cited previously) are maintained.
The claims of U.S. Patent No. 10,570,213 are drawn to a method for treating or delaying progression of non-squamous non-small cell lung cancer (NSCLC) in an
individual comprising administering to the individual 1200 mg of an anti-PD-LI antibody every three weeks, the anti-PD-L1 antibody comprising a heavy chain comprising
HVR-H1 sequence of SEQ ID NO:19, HVR-H2 sequence of SEQ ID NO:20, and HVR-H3 sequence of SEQ ID NO:21, and a light chain comprising HVR-LI sequence of SEQ ID NO:22, HVR-L2 sequence of SEQ ID NO:23, and HVR-L3 sequence of SEQ ID NO:24, wherein the antibody is administered in combination with a taxane selected from paclitaxel or nab-paclitaxel and carboplatin, wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4
As disclosed in the sequence comparison below the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4 comprise the listed CDRs for the present claims.
Zitvogel disclose that MPDL3280A is one of six agents that block the PD-1/PD-L1 pathway in clinical studies (page 1224, 2nd column, 2nd paragraph). MPDL3280A comprises the 6 CDRs of claim 1 of U.S. Patent No. 10,570,213.
Applicant requests that the Office reconsider the double patenting rejections in view of the claim amendments and foregoing remarks or hold this nonstatutory double patenting rejection in abeyance until an indication of otherwise allowable subject matter.
For reasons above and of record, the rejections are maintained.
The rejections of claims 3 and 21-28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 and 36-38 of U.S. Patent No. 8,217,149 in view of Felip et al (the Lancet 398:1344-1357, 2019, IDS, cited previously) and West et al (Lancet Oncol 20:924-937, 2019, IDS, cited previously).
Claim 3 is drawn to a method for treating a non-small cell lung cancer in an individual comprising administering to the individual an effective amount of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 15);
(b) an HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 16);
(c) an HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 17);
(e) an HVR-L2 sequence of SASFL YS (SEQ ID NO: 18); and
(f) an HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 19).
Claim 21 is drawn to a method for treating a non-small cell lung cancer in an individual comprising intravenously administering to the individual about 1200 mg of an anti-PD-L 1 antibody every three weeks, wherein the anti-PD-L 1 antibody is MPDL3280A (atezolizumab).
The claims of US 8,217,149 are drawn to an isolated heavy chain variable region polypeptide that specifically binds to PD-L1 comprising an HVR-H1, HVRH2 and HVR-H3 sequence, wherein the HVR-H1 sequence is GFTFSX1SWIH, the HVR-H2 sequence is AWIX2PYGGSX3YYADSVKG and the HVR-H3 sequence is RHWPGGFDY. The identical CDRs as disclosed in the present application. The specification of US 8,217,149 discloses that the anti-PD-L1 antibody may be used to treat lung cancer (column 10, lines 5-9)
Fehrenbacher disclose the treatment of patients with NSCLC with 1200 mg of atezolizumab intravenously every three weeks (page 1838, 1st column to 1839, 1st column). Fehrenbacher disclose that treatment response was associated with PD-L1 expression (Id).
West disclose the treatment of patients with NSCLC with 1200 mg intravenously every 3 weeks in combination with carboplatin plus nabpaclitaxel (page 926, 1st column, 3rd paragraph; page 926, 2nd column, 5th paragraph). West disclose measuring expression of PD-L1 on tumor cells and tumor infiltrating cells by immunohistochemistry (page 926, 2nd column, 4th paragraph; page 927, 2nd column, 4th paragraph).
Fehrenbacher disclose the treatment of patients with NSCLC with 1200 mg of atezolizumab intravenously every three weeks (page 1838, 1st column to 1839, 1st column). Fehrenbacher disclose that treatment response was associated with PD-L1 expression (Id).
One of ordinary skill in the art would have been motivated to apply Fehrenbacher and West’s treatment of NSCLC therapeutic regimen to the claimed antibody of US 8,217,149 because they all disclose the treatment of NSCLC with an anti-PD-L1 antibody comprising the recited CDRs in the claimed antibody of US 8,217,149.
Applicant argues that as discussed supra, West and Felip are not considered prior art for the present application.
In response, as discussed above, West and Felip are considered prior art for the present application.
The rejections of claims 3 and 21-28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10,570,213 in view of in view of in view of West et al (Lancet Oncol 20:924-937, 2019, IDS, cited previously) and Felip et al (the Lancet 398:1344-1357, 2019, IDS, cited previously) are maintained.
The claims of U.S. Patent No. 10,570,213 are drawn to a method for treating or delaying progression of non-squamous non-small cell lung cancer (NSCLC) in an
individual comprising administering to the individual 1200 mg of an anti-PD-LI antibody every three weeks, the anti-PD-LI antibody comprising a heavy chain comprising
HVR-H1 sequence of SEQ ID NO:19, HVR-H2 sequence of SEQ ID NO:20, and HVR-H3 sequence of SEQ ID NO:21, and a light chain comprising HVR-LI sequence of SEQ ID NO:22, HVR-L2 sequence of SEQ ID NO:23, and HVR-L3 sequence of SEQ ID NO:24, wherein the antibody is administered in combination with a taxane selected from paclitaxel or nab-paclitaxel and carboplatin, wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4
As disclosed in the sequence comparison below the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4 comprise the listed CDRs for the present claims.
West disclose the treatment of patients with NSCLC with 1200 mg intravenously every 3 weeks in combination with carboplatin plus nabpaclitaxel (page 926, 1st column, 3rd paragraph; page 926, 2nd column, 5th paragraph).
Felip disclose the treatment of patients with completely resected stage IB to IIIA NSCLC with 1200 mg atezolizumab intravenously every 21 days for 16 cycles or 1 year after 75 mg/m2 cisplatin chemotherapy intravenously for up to four 21 days cycles (page 1346).
One of ordinary skill in the art would have been motivated to apply Felip and West’s treatment of NSCLC therapeutic regimen to the claimed antibody of US 8,217,149 because they all disclose the treatment of NSCLC with an anti-PD-L1 antibody comprising the recited CDRs in the claimed antibody of US 8,217,149.
Applicant argues that as discussed supra, West and Felip are not considered prior art for the present application.
In response, as discussed above, West and Felip are considered prior art for the present application.
Summary
Claims 1-3, 6-15, 17-28, 31 and 32 stand rejected.
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