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 .
Priority- Foreign
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(a)-(d) and (f) or under 35 U.S.C. 120, 121, 365(a) or (b), or 386(a) is acknowledged. The present application is drawn from PCT/CN2022/107363, filed 7/22/2022; and claims benefit under 35 U.S.C. (119(a)-(d) to foreign application CN202110831932, filed 7/22/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
However, applicants have not provided an English translation of the foreign application. Applicants cannot rely upon the certified copy of the foreign priority application to overcome any rejections because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Status of Claims
Claims 44-63 are pending and are being examined on the merits.
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.
Claim 62 is 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 62 recites wherein the anti-PD-L1 antibody comprises a heavy chain of humanized antibodies selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 and hu5G11-hIgG4. The specifications make reference to WO 2016022630. WO ‘630 teaches humanizing murine anti-PD-L1 antibodies 13C5 and 5G11; therefore WO ‘630 teaches various embodiments of humanized 13C5. WO ‘630 does not recite, specifically, an antibody named “hu13C5-hIgG1.” Thus, it is unclear if the instant claims are drawn to an antibody named “hu13C5-hIgG1”, or if the instant claims are referencing any 13C5 antibody that has been humanized, or if the instant claims are referencing specific species as listed in WO ‘630. Therefore it is unclear exactly what the sequence of the antibody VH and VL of claim 62 is, or is required to be in order to meet the claim limitations. “Hu13C5-hIgG1” could be considered lab nomenclature, which is not appropriate for recitation in a claim. As the metes and bounds of the requirements of claim 62 are unclear claim 62 is rejected for indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 59 and 61-62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 59 recites an anti-PD-L1 antibody comprising the HCDRs 1-3 selected from SEQ ID NOs: 1 or 4, 2 or 5, 3 or 6; and the LCDRs 1-3 selected from SEQ ID NOs: 7 or 10, 8 or 11, 9 or 12. Similarly, claim 62 recites wherein the VH is selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 and hu5G11-hIgG4 and the VL is selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 and hu5G11-hIgG4. Thus, both of claims 59 and 62 allow mixing-and-matching CDRs or the full VH and VL from alternative antibody species into a single antibody of the claims. The claims are therefore interpreted as a genus of antibodies comprising variant species with individually selected CDR domains, in various combinations, selected from the alternatives listed in the claims. Claim 61 recites an anti-PD-L1 antibody comprising a VH or VL having at least 80% homology to that of SEQ ID NOs: 13-16. Claim 61 is interpreted to encompass mutations within the CDRs of the variable domains, and thus encompasses unidentified CDRs. Thus, the distinct and complementary set of 6 CDRs of any single embodiment of the antibody are not limited or defined, in view of their ability to be individually mixed and matched from the claimed set of sequences, or mutated with alternate residues.
In support of the genus of antibodies with variant sets of CDRs selected from the alternatives listed, the specifications embody only antibody hu5G11-hIgG1 (pg. 50, section 1.2), as it was described in WO2016022630 (pg. 20, para. 3; pg. 24, para. 1; pg. 49, para. 3). Reference is made to antibody 13C5 as comprising the HCDRs 1-3 of instant SEQ ID NOs: 4-6 and the LCDRs 1-3 of instant SEQ ID NO: 10-12; and antibody 5G11 as comprising HCDRs 1-3 of SEQ ID NOs: 1-3 and the LCDRs 1-3 of SEQ ID NOs: 7-9 (pg. 24, para. 1), which are also referenced as being described in WO2016022630 (to Zha et al., see below). WO2016022630 does not teach embodiments of anti-PD-L1 antibodies having some CDRs of 13C5 mixed with some CDRs of 5G11.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of six CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the claimed embodiments, in which CDRs of antibody 13C5 and antibody 5G11 were mixed and matched, which were reduced to practice; nor do they identify the shared structural properties of the variants that would define the genus beyond the desired functionality. Currently the essential property of binding PD-L1 is imparted by the specific corresponding sets of CDRs of the murine antibodies 13C5 and 5G11, which are themselves structurally distinct. For example, the HCDR3 of 13C5 is GYDSGFAY (SEQ ID NO: 6) and the HCDR3 of 5G11 is LGFYAMDY (SEQ ID NO: 3); the two HCDRs are entirely structurally distinct. Similarly, the LCDR3 of 13C5 is QHSWEIPYT (SEQ ID NO: 12) and that of 5G11 is QQDYTSPYT (SEQ ID NO: 9); the two LCDRs share only 4 of 9 amino acid residues (44%). Given that the claims encompass the HCDRs of 13C5 being matched with the LCDRs of 5G11, of the VH of hu5G11 being matched with the VL of hu13C5, it is clear that the various embodiments may not have a single structural similarity which imparts their functionality of binding PD-L1. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding PD-L1 should be disclosed. Further, regarding claim 61, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 80% similarity to SEQ ID NOs: 13-16”, whereby the resulting variant antibody binds PD-L1, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (with various combinations of CDR sequences) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an embodiment species comprising the HCDRs of SEQ ID NOs: 1-3 and the LCDRs of SEQ ID NOs 10-12, would lose functional binding to PD-L1, as that complementary set of CDRs is not taught in the art. Similarly, with regard to claim 61, it may be that sequences that are > 80% similar to, for example the VH of SEQ ID NO: 13, but have 2-3 deleterious mutations in a critical CDR domain would also lose functional binding to PD-L1.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, claims 59 and 61-62 are rejected for lack of adequate written description support. Claims 60 and 63 depend from rejected claims 59 and 63, respectively, however they rectify the indefiniteness issues by claiming distinct embodiments, with defined sets of CDRs and/or variable domains that are to be used together.
Claim Rejections - 35 USC § 102
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 44-50 and 54-63 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by NCT04891900 (from IDS; Henan Cancer Hospital; 5/19/2021), as evidenced by Zha et al., (from IDS; WO 2016/022630; published 2/11/2016).
NCT04891900 teaches a clinical trial using TQB2450 and Anlotinib, combined with chemotherapy in the treatment of gastric or gastroesophageal junction adenocarcinoma (title). It is known in the art that TQB2450 is otherwise known as Benmelstobart, and it is a humanized monoclonal antibody designed to target programmed death ligand-1 (PD-L1; see also Zha et al.). NCT04891900 teaches the treatment includes the anti-PD-L1 antibody TQB2450 plus Anlotinib hydrochloride, plus the chemotherapy agents Oxaliplatin and Capecitabine (pg. 2, Brief Summary). NCT04891900 teaches the “initial treatment” is TQB2450 (1200 mg), Anlotinib (10 mg), Oxaliplatin (130 mg) and Capecitabine (1000 mg); all of which are administered Day 1 (pg. 3, Arms and Interventions). The initial treatment is 6 cycles.
Regarding claim 44; the method for treating gastric carcinoma of NCT04891900 anticipates the method of claim 44, whereby the treatment comprises administering an effective amount of an anti-PD-L1 antibody and anlotinib.
Regarding claims 45-47; the methods of NCT04891900 comprise administering a third therapeutic agent, which is capecitabine and oxaliplatin. Thus, NCT04891900 anticipates instant claims 45-47.
Regarding claims 48-50; NCT04891900 teaches that all the agents are administering in an initial treatment, which is 6 cycles, and the dose of the anti-PD-L1 antibody is 1200 mg. Thus, NCT04891900 anticipates instant claims 48-50.
Regarding claims 54-56; NCT04891900 teaches a cycle is every 3 weeks, or 21 days (pg. 3, Arms and Interventions). The anti-PD-L1 antibody is administered Day 1, once every 3 weeks; the Anlotinib is administered days 1-14 in a 21-day cycle; Oxaliplatin is administered Day 1, once every 3 weeks; and Capecitabine is administered days 1-14 in a 21 day cycle. Thus NCT04891900 anticipates instant claims 54-56.
Regarding claims 57-58; NCT04891900 teaches patients include histology or cytology confirmed HER2 negative status, locally advanced or metastatic gastric adenocarcinoma, including signet ring cell carcinoma or mucinous adenocarcinoma (pg. 4, Inclusion Criteria). Thus, NCT04891900 anticipates instant claims 57-58.
Regarding claims 59-63; TQB2450 is also known as Benmelstobart, and has the VH and VL amino acid sequences as defined in Zha et al., SEQ ID NO: 42 and 44, respectively. See also the STN sequence search results (pg. 5) whereby the structure is identified as Benmelstobart or TQB 2450. Zha teaches humanized anti-PD-L1 antibodies based on the murine sequence for 5G11, such as hu5g11-IgG1. Zha teaches the full hu5G11-hIgG1 HC is that of SEQ ID NO: 70 and the hu5G11-hIgG1 LC is that of SEQ ID NO: 74 (pgs. 31-36, Table 3); a STN sequence search identified Zha SEQ ID NOs: 70 and 74 as Benmelstobart, or TQB2450.
The HC of hu5G11-hIgG1, of Zha SEQ ID NO: 70, is 100% identical to that of instant SEQ ID NO: 13 and comprises the instant HCDRs of SEQ ID NOs: 1-3, as well as the VH of instant SEQ ID NO: 13, with 100% sequence identity. The LC of hu5G11-hIgG1, of Zha SEQ ID NO: 74, is 100% identical to that of instant SEQ ID NO: 15 and comprises the instant LCDRs of SEQ ID NOs: 7-9, as well as the VL of instant SEQ ID NO: 15, with 100% sequence identity. Thus, Zha SEQ ID NOs: 70 and 74, as well as instant SEQ ID NOs: 17 and 18, encode the HC and LC, respectively, of Benmelstobart, with 100% sequence identity.
Thus, the examiner asserts that the hu5G11-hIgG1 antibody of Zha is Benmelstobart (i.e., TQB2450), and NCT04891900 teaches a method of treating gastric cancer comprising administering TQB2450 and Anlotinib. Thus, the TQB2450 antibody of NCT04891900 is the anti-PD-L1 antibody of instant claims 59-63 (comprising SEQ ID NOs: 1-3, 7-9, 13, 15 and 17-18), and therefore the methods of NCT04891900 anticipate instant claims 59-63, as evidenced by Zha et al.
Claim Rejections - 35 USC § 103
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.
Claims 44-63 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04891900 (from IDS; Henan Cancer Hospital; 5/19/2021) and Chen et al., (US 2016/0326138; published 11/10/2016).
The reasons why NCT04891900 anticipates instant claims 44-50 and 54-63 are described above.
Regarding claim 51; NCT04891900 teaches that 1200 mg of TQB2450 is administered via ivgtt (i.e., intravenous drip administration). MPEP section 2144.05 teaches the obviousness of similar and overlapping ranges, amounts and proportions. Section 2144.05(II) teaches optimization within the prior art conditions or through routine experimentation is obvious. “Generally, the differences in concentration will not support the patentably of the subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.” As NCT04891900 teaches administration of TQB2450 as a pharmaceutical composition, whereby administration of 1200 mg is via an intravenous drip administration route, it is obvious to formulate the concentration of TQB2450 to be optimal for any desired duration of drip administration. For example, if 1200 mg of TQB2450 is formulated in 250 mL, which takes 60 minutes to administer, its concentration would be 4.8 mg/mL. However, if 1200 mg of TQB2450 is formulated in 120 mL, such that the i.v. drip administration occurs in 30 minutes, the concentration would be 10 mg/mL. Thus, as NCT04891900 teaches administering 1200 mg of TQB2450, it is obvious to formulate the 1200 mg of TQB2450 at a concentration of 10 mg/mL in 120 mL of saline. The motivation for doing so being to optimize the ivgtt administration protocol based on the desired duration of i.v. drip administration. Thus, NCT04891900 makes obvious instant claim 51.
Regarding claims 52-53; NCT04891900 teaches the anti-PD-L1 antibody, TQB2450, as well as the third agent, Oxaliplatin, are each formulated in a pharmaceutical composition, which is administered ivgtt (pg. 3, Arms and Interventions).
However, NCT04891900 does not teach anlotinib as a pharmaceutical composition, rather Anlotinib is administered orally, at 10 mg/day.
Chen et al. teaches new processes to synthesize AL3818 (a.k.a. Anlotinib), resulting in a stable crystalline form of AL3818, including salts (abstract). Chen also teaches anti-cancer activities of AL3818 and its salts (abstract). Chen teaches that the present invention relates to administering AL3818 with PD-1 or PD-L1 agents in a method for treating solid tumors, which may be gastric cancer (pg. 10, Example 15, para. 0074). Chen teaches AL3818 and its salts as a pharmaceutical composition (pg. 16, claim 17), and methods of administering the pharmaceutical composition for treating cancer (claim 19), wherein the cancer is gastric cancer (claim 20) and wherein the method includes combining chemotherapy agents such as paclitaxel (claim 22), and/or immunotherapy agents such as the anti-PD-1 antibody nivolumab (claim 23).
Thus, it would have been obvious to one of skill in the art to formulate Anlotinib (i.e. AL3818) as a pharmaceutical composition which may be administered simultaneously, nonsimultaneously or sequentially to the anti-PD-L1 antibody composition and the Oxaliplatin composition of NCT04891900. One would have been motivated to do so for optimizing the administration protocols of a multi-drug treatment regime as desired. There would have been a reasonable expectation for success given that Anlotinib, or the pharmaceutically acceptable salt thereof, may be formulated in a pharmaceutical composition for administering in a method of treating cancer, as taught by Chen et al. Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made.
The combination of NCT04891900 and Chen, whereby each of the PD-L1 antibody TQB2450, Anlotinib and Oxaliplatin are formulated as a pharmaceutical composition, make obvious instant claims 52-53.
Claims 44, 50, 51, 52, 55, 57, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Tian et al. (WO 2020/015703, publication date: 01/23/2020), Gao et al. (Oncology Letters, 20: 1001-1014, 2020), and Waldum et al. (Int. J. Mol. Sci., 19(4109): 1-12, 2018).
At p. 7 and 8, Tian et al. teach that “[t]he object of the present application is at least to provide a pharmaceutical combination comprising a tyrosine kinase inhibitor and an inhibitor of the interaction between PD-1 and its ligand PD-L1. In some embodiments, the tyrosine kinase inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof, and in some specific embodiments, the tyrosine kinase inhibitor is a salt of a compound of Formula I Acid salt, anlotinib hydrochloride. In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody that binds to programmed death receptor 1 (PD-1) and / or inhibits PD-1 activity or the antigen-binding portion is, alternatively, an antibody or an antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and / or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some specific embodiments, the antibody or antigen-binding portion thereof is (a) a monoclonal antibody or an antigen-binding fragment thereof that specifically binds human PD-1 and blocks the binding of human PD-L1 to human PD-1 or (b) a monoclonal antibody or an antigen-binding fragment thereof that specifically binds human PD-L1 and blocks the binding of human PD-L1 to human PD-1.”
However Tian et al. do not specifically teach that a combination of anlotinib and an anti-PD-L1 antibody may be used in the treatment of gastric carcinoma.
At the Abstract, Gao et al. teach that “[a]nlotinib has encouraging efficacy and a manageable and tolerable safety profile in a broad range of malignancies, including medullary thyroid cancer, renal cell cancer, gastric cancer and esophageal squamous cell carcinoma.” At p. 1002, Gao et al. teach that “[a]nlotinib (AL3818) is a novel oral RTK inhibitor targeting VEGFR-2 and -3, FGFR1-4, PDGFR-α and -β, c-Kit and Ret (18), thereby exerting inhibitory effects on tumor growth and angiogenesis … several phase II/III clinical trials of anlotinib have been completed or are ongoing for various cancer types, including STS, renal cell carcinoma (RCC), hepatocellular carcinoma, ovarian cancer, esophageal squamous cell carcinoma (ESCC), gastric cancer…”
Waldum et al. teach that there are numerous types of gastric cancers, including papillary, tubular, mucinous, and singlet-ring cell subtypes of gastric carcinoma, see p. 2.
Thus, it would have been obvious to one of skill in the art to formulate treat gastric carcinoma by administering to a subject in need thereof a combination of anlotinib and an anti-PD-L1 antibody. One of ordinary skill in the art would have been motivated to do so, because Tian et al. teach that a combination of anlotinib and an anti-PD-L1 antibody may be used to treat cancer. Furthermore Gao et al. teach that anlotinib may be used to treat gastric cancer. As such there would have been a reasonable expectation that gastric cancer may be treated by administering a combination of anlotinib and an anti-PD-L1 antibody to a subject in need thereof. Additionally in view of the teachings of Waldum et al., one or ordinary skill in the art would have been motivated to treat various types of gastric cancers, including papillary, tubular, mucinous, and singlet-ring cell subtypes of gastric carcinoma.
Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made. The invention of Tian et al., Gao et al., and Waldum et al. meets the limitations of claim 44.
With respect to claims 50, 51, and 55, MPEP section 2144.05 teaches the obviousness of similar and overlapping ranges, amounts and proportions. Section 2144.05(II) teaches optimization within the prior art conditions or through routine experimentation is obvious. “Generally, the differences in concentration will not support the patentably of the subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.” One of ordinary skill in the art would have had ample motivation to optimize administration schedules and dosages of the claimed medicaments in order to arrive at an invention that is safe and efficacious.
With respect to claim 52, at p. 10 and 11, Tian et al. teach pharmaceutical compositions that comprise an anti-PD-L1 antibody and a tyrosine kinase inhibitor, and at p. 27, Tian et al. teach that “[a]s used herein, ‘combined’ or ‘combined use’ means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.”
With respect to claim 57, as indicated above, Waldum et al. teach that there are numerous types of gastric cancers, including papillary, tubular, mucinous, and singlet-ring cell subtypes of gastric carcinoma, see p. 2.
With respect to claim 58, one of ordinary skill in the art would have been motivated to administer the invention of Tian et al. and Gao et al. to gastric carcinoma patients regardless of levels of HER2 expression.
Claims 45-49, 53, 54, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Tian et al. (WO 2020/015703, publication date: 01/23/2020), Gao et al. (Oncology Letters, 20: 1001-1014, 2020), and Waldum et al. (Int. J. Mol. Sci., 19(4109): 1-12, 2018), with respect to claims 44, 50, 51, 52, 55, 57, and 58, and further in view of Montagnani et al. (Gastric Cancer, 14: 50-55, 2014).
The teachings of Tian et al., Gao et al., and Waldrum et al. are detailed above. These references do not teach or suggest the administration of oxaliplatin.
However, Montagnani et al. teach that “[c]isplatin has been largely used in the treat ment of advanced, unresectable gastric cancer, mainly in combinations with fluoropyrimidines and anthracyclines. Oxaliplatin has been shown to be at least as effective as cisplatin for this disease, but with less toxicity and a better tolerability profile, especially for older patients.” See
Thus, it would have been obvious to one of skill in the art to formulate treat gastric carcinoma by administering to a subject in need thereof a combination of anlotinib, an anti-PD-L1 antibody, and oxaliplatin. One of ordinary skill in the art would have been motivated to do so, because Tian et al. teach that a combination of anlotinib and an anti-PD-L1 antibody may be used to treat cancer. Furthermore Gao et al. teach that anlotinib may be used to treat gastric cancer. Montagnani et al. teach that gastric cancers may be treated with oxaliplatin. As such there would have been a reasonable expectation that gastric cancer may be treated by administering a combination of anlotinib, an anti-PD-L1 antibody, and oxaliplatin to a subject in need thereof. Additionally in view of the teachings of Waldum et al., one or ordinary skill in the art would have been motivated to treat various types of gastric cancers, including papillary, tubular, mucinous, and singlet-ring cell subtypes of gastric carcinoma.
Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made. The invention of Tian et al., Gao et al., Waldum et al., and Montagnani et al. meets the limitations of claim 45-47.
With respect to claims 48, 49, 53, 54, and 56, MPEP section 2144.05 teaches the obviousness of similar and overlapping ranges, amounts and proportions. Section 2144.05(II) teaches optimization within the prior art conditions or through routine experimentation is obvious. “Generally, the differences in concentration will not support the patentably of the subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.” One of ordinary skill in the art would have had ample motivation to optimize administration schedules and dosages of the claimed medicaments in order to arrive at an invention that is safe and efficacious.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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