DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-10 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a continuation of abandoned U.S. Patent Application No. 16/609,671 (filed on 10/30/2019) as a 371 National Stage Entry of International Patent Application No. PCT/US2018/030420 (filed on 05/01/2018), which claims the benefit of U.S. Provisional Patent Application No. 62/500,268 (filed on 05/02/2017).
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, 365(c), or 386(c) is acknowledged. Claims 1-10 have an effective filing date of 05/02/2017 corresponding to Provisional U.S. Application No. 62/500,268.
Information Disclosure Statement
The information disclosure statements filed on 09/11/2024, 11/25/2024 (2 information disclosure statements), 03/05/2025, 05/07/2025, 05/30/2025, 06/25/2025, 07/01/2025, 10/10/2025, and 01/28/2026 have been considered. Signed copies are enclosed; all references considered unless marked with strikethrough.
The information disclosure statement filed 09/11/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Claim Objections
Claim 4 is objected to because of the following informalities: the word “or” is missing from the list of concentrations. Appropriate correction is required.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating head and neck squamous cell cancer, melanoma, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, non-small cell lung cancer, prostate cancer, non-Hodgkin lymphoma, HIV, and/or HBV/HCV using a coformulation of pembrolizumab and anti-CTLA4 antibody, does not reasonably provide enablement for a method of treating all cancer and chronic infections using a coformulation of pembrolizumab and anti-CTLA4 antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature or the invention
Claim 10 is drawn to a “method of treating cancer or chronic infection in a human patient in need thereof, the method comprising administering an effective amount of the co-formulation of claim 1.” (lines 1-3).
As such, claim 10 generally reads on the treatment of all cancer and chronic infections comprising administering to a human the coformulation of claim 1, the full scope of which is not enabled by the method as instantly claimed.
(2) The state of the prior art
Pembrolizumab and anti-CTLA4 antibody are immune checkpoint inhibitors, implicated in stimulating an immune response against cancer and infections.
Pembrolizumab has known efficacy in head and neck squamous cell cancer, melanoma, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, and non-small cell lung cancer (Prescribing Information for KEYTRUDA™, Merck & Co., 2014, Pg. 1, Indications and Usage). Anti-CTLA4 antibody has known efficacy in prostate cancer, melanoma, and non-Hodgkin lymphoma (ClinicalTrial.gov search results before EFD 05/05/2017, search created 2026).
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. Even within a given cancer type, “[i]ntertumor and intratumor heterogeneity are important obstacles to overcome when designing the most effective therapeutic strategies for patients with cancer. The genotypic and phenotypic variability of tumors can have important consequences for diagnosis, prognosis, and treatment” (Lovly et al., Pg. e586, Integrating the Heterogeneity of Cancer in Clinical Decision Making, first paragraph).
For example, immune checkpoint inhibitors would not be effective against “cold tumors” i.e. tumors with low immune cell presence. Wang et al. indicate “’[h]ot tumors’ are characterized… PD‐L1 overexpression, genomic instability, and preexisting antitumor immune responses. ‘Cold tumors’ have the opposite characteristics. Variable tumors are tumors in a variable state between cold and hot ones. It is generally accepted that [immune checkpoint inhibitors] alone are more effective against ‘hot tumors’ while having no benefit in treating ‘cold’ tumors or ‘variable’ tumors” (Wang et al., 2023, Pg. 2, end of column 1 – beginning of column 2).
Therefore, it is not sufficiently supported in the prior art that pembrolizumab, anti-CTLA4 antibody, or a combination of the two could treat all cancer types.
Davar et al. state typically clinical trials “evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with… chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV)” (Case Reports in Oncological Medicine, 2015, Pg. 1, Abstract). In Davar et al., patients with advanced melanoma and concomitant HCV/HIV infections were treated with pembrolizumab, demonstrating antitumor benefit and/or maintaining low viral loads (Pg, 2-4, Conclusions).
The prior art does not indicate other chronic infections, besides HIV and HBV/HCV can be treated with pembrolizumab and/or anti-CTLA4 antibody.
Chronic infections are varied in infectious agent and presentation. A broad spectrum of infectious agents and their chronic outcomes compose this evolving field. O'Connor et al. state regarding chronic infections that “[e]very organ system or tissue has been a target. Bacteria, fungi, parasites, viruses, and the recently discovered prions are all implicated, and as yet unidentified etiologic agents will likely be described over the coming years” (Emerg Infect Dis, 2006, Pg. 4, Breadth of the Field, ¶ 1).
For example, immune checkpoint inhibitors would have no effect on prion diseases, caused by misfolded proteins that the immune system cannot recognize.
Therefore, it is not sufficiently supported in the prior art that pembrolizumab, anti-CTLA4 antibody, or a combination of the two could treat all chronic infections.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of pembrolizumab and/or anti-CTLA4 antibody to treat a subset of cancer and chronic infections is well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of pembrolizumab and anti-CTLA4 antibody to treat any cancer or chronic infection within the scope of claim 10 is not predictable.
The predictability of applying pembrolizumab and anti-CTLA4 antibody for the treatment of any cancer or chronic infections would be low given that these diseases vary greatly in cause and mechanism of action, some of which would not respond to treatment with the coformulation (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The specification shows neither in vivo nor in vitro experiments regarding the use of a coformulation of pembrolizumab and anti-CTLA4 antibody to treat cancer and chronic infections. The specification lacks any examples or guidance; instead, the instant application relies on the teachings of the prior art. To the examiner’s knowledge, a coformulation of pembrolizumab and anti-CTLA4 has been implicated in the treatment of disease (see WO 2015/066413 A1 in 103 claim rejections) but not utilized in vivo prior to the effective filing date of the application (the amount of direction or guidance presented and the presence or absence of working examples).
The amount of experimentation would not be reasonable because it would require determining which cancers and chronic infections could be treated by a coformulation of pembrolizumab and anti-CTLA4 antibody. It is not routine to determine how this coformulation would treat such a broad class of disease. Undue experimentation would be required to determine whether the coformulation would treat cancers and chronic infections (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of claim 10 is extremely broad; it recites cancers and chronic infections that require the specification of the instant application to provide support for the entire scope of the claim. The specification fails to show that a person having ordinary skill in the art could treat all recited diseases without undue experimentation.
Moreover, as described above, the diseases do not share a common cause nor functional link. Evidence of treatment efficacy with pembrolizumab and/or anti-CTLA4 antibody in head and neck squamous cell cancer, melanoma, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, non-small cell lung cancer, prostate cancer, non-Hodgkin lymphoma, HIV, and/or HBV/HCV is in the prior art.
Therefore, the method of treating head and neck squamous cell cancer, melanoma, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, non-small cell lung cancer, prostate cancer, non-Hodgkin lymphoma, HIV, and/or HBV/HCV using a coformulation of pembrolizumab and anti-CTLA4 antibody is supported. The method of treating all cancer and chronic infections using a coformulation of pembrolizumab and anti-CTLA4 antibody is not supported.
Claim 10 is not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to treat all cancer and chronic infections using a coformulation of pembrolizumab and anti-CTLA4 antibody with a predictability of success for the reasons outlined above.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 and 5 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 2 recites the limitation "the ratio" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 3 is included in this rejection as it depends on or incorporates claim 2.
Claim 5 recites the limitation "the… antigen binding fragment" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. In claim 1, “the anti-PD1 antibody” (line 5) is defined, but there is no mention of an antigen binding fragment.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites “an anti-PD1 antibody, wherein the anti-PD1 antibody is pembrolizumab” (lines 5-6). Pembrolizumab is a humanized IgG4 mAb (Specification, ¶ 0131). Claim 5 recites the limitation "the anti-PD1 antibody or antigen binding fragment" (lines 1-2). This broadens the scope of claim rather than further limiting it as it includes any antigen binding fragment of pembrolizumab. Claim 5 fails to include all limitations of the claim upon which it depends (claim 1).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Publication 2009/0130119 A1 (referred to as Pub. ‘119) in view of WO 2016/015675 A1 (referred to as WO ‘675), WO 2015/066413 A1 (referred to as WO ‘413), U.S. Patent Application Publication 2015/0071925 A1 (referred to as Pub. ‘925), and Zhou et al. (Journal of Pharmaceutical Sciences, 2010) as evidenced by French and Robson (Journal of Molecular Evolution, 1983), Bose and Sinha (Immunology, 2005), and Ewert et al. (Methods, 2004).
Claim 1
Pub. ‘119 teaches a pharmaceutical composition of anti-CTLA4 antibody comprising:
20 mg/mL of anti-CTLA4 antibody (Pg. 3, ¶ 0032, last 3 lines, “wherein the antibody binds CTLA-4… [and] contains a concentration of antibodies of about 20 mg/mL”),
10 mM of L-histidine (Pg. 20, ¶ 0217, line 10, “10 mM of L-histidine”),
about 50-150 mg/mL sucrose (Pg. 20, ¶ 0221, lines 1-10, “tonicity agent is… sucrose”; Pg. 20, ¶ 0225, lines 1-5, “concentration of the tonicity agent is… about 50 mg/mL to about 150 mg/mL,” equal to about 5-15% w/v as calculated in formula below),
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about 1-100 mM methionine (Pg. 21, ¶ 0234, last 2 lines, “methionine in a concentration that ranges from 1 mM to about 100 mM”)
at a pH of 5.5 (Pg. 1, ¶ 0004, last line, “pH 5.5”).
Pub. ‘119 further teaches methionine and sucrose in a pharmaceutical formulation is important for discoloration prevention and osmotic pressure adjustment respectively (Pg. 38, ¶ 0401; Pg. 20, ¶ 0219).
The disclosure of the Pub. '119 differs from the instant claim 1 in that it does not teach the anti-CTLA4 antibody comprising SEQ ID NOs: 48 and 88 nor a coformulation with pembrolizumab.
While methionine is not described as L-methionine, it would have been obvious to a person having ordinary skill in the art that L-methionine was used in Pub. ‘119 as it is the standard form of methionine, naturally occurring and used in pharmaceutical compositions.
It is noted that Pub. ‘119 does not teach the exact concentrations of 10 mM L-methionine and 7% w/v sucrose as stated in claim 1. However, the identity and the working concentrations for L-methionine and sucrose are disclosed by Pub ‘119 (e.g. 1-100 mM L-methionine and 5-15% w/v sucrose), crucial for reducing percent oxidation (Pg. 40, ¶ 0413, lines 1-3,“addition of methionine… reduces percent oxidation”) and adjusting osmotic pressure of antibody formulations (Pg. 20, ¶ 0219, line 5, “tonicity agent can adjust the osmotic pressure”) respectively. MPEP 2144.05(II)(A) states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. L-methionine and sucrose), so as to achieve optimal effect and maximal benefit (i.e. reducing percent oxidation and adjusting osmotic pressure of an antibody formulation). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of antibody formulation components would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the application would immediately envisage the claimed concentrations of 10 mM L-methionine and 7% w/v sucrose to achieve them without undue experimentation in order to reduce percent oxidation and adjust osmotic pressure of an antibody formulation
WO ‘675 teaches an anti-CTLA4 antibody comprising SEQ ID NOs: 48 and 88 of the instant application (see SEQ ID NOs: 16 and 14 of WO ‘675 respectively). Note that SEQ ID NO: 14 of WO ‘675 is 99.7% identical to SEQ ID NO: 88 of the instant application, with an amino acid substitution at position 18 (instant application L18, WO ‘675 M18) in the framework region of the antibody.
The disclosure of the WO ‘675 differs from the instant claim 1 in that it does not teach the pharmaceutical formulation of the anti-CTLA4 antibody nor a coformulation with pembrolizumab.
French and Robson indicate L and M represent a conservative amino acid substitution, conserving hydrophobicity and molecular bulk of the side chain (Pg. 173, Fig. 1). Bose and Sinha state mutations outside of CDR regions are unlikely to impact antigen binding (Pg. 173, column 1, ¶ 1).
The conservative substitution of L and M was known prior to the effective filing date of the instant application. There is no evidence that M18L substitution affected the antibody structure or conferred a meaningful difference to performance. However, Ewert et al. state “the stability of a suboptimal framework can be improved by the introduction of point mutations designed to optimize key residue interactions” (Pg. 184, Abstract), giving motivation for why a person having ordinary skill in the art might introduce an M18L substitution.
As the CDRs are conserved, the ability to bind CTLA4 is retained. Note that the experiments in the instant application concerning the coformulations of anti-CTLA4 antibody and pembrolizumab define the anti-CTLA4 antibody by its CDRs not by SEQ ID NOs: 48 and 88 (Specification, ¶ 0280).
“The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art” (MPEP 2143[I]{B]).
Therefore, a person having ordinary skill in the art prior to the effective filing date of the application could have substituted one known element for another (i.e. a conservative amino acid substitution M18L in the framework region of the anti-CTLA4 antibody) and the results of the substitution would have predictable success (i.e. does not impact the ability of the antibody to bind CTLA4). A person having ordinary skill in the art would be motivated to make this substation to modify antibody stability without effecting antigen binding.
WO ‘413 teaches an anti-PD1 antibody can be administered in combination with an anti-CTLA-4 antibody” (Pg. 36, ¶ 2, lines 3-4), wherein the antibodies are formulated together (Pg. 33, ¶ 4, line 2) and the anti-PD1 is pembrolizumab (Pg. 34, last ¶, lines 1-2).
WO ’413 further teaches these formulations can be used for treating bacterial infections (Abstract), giving motivation to combine anti-CTLA4 and pembrolizumab for therapeutic purposes.
The disclosure of the WO ‘413 differs from the instant claim 1 in that it does not teach the excipients of the pharmaceutical coformulation nor the SEQ ID NOs: 48 and 88 for the anti-CTLA4 antibody.
Pub. ‘925 teaches a pharmaceutical formulation of pembrolizumab with antibody concentrations of about 10-100 mg/mL (Pg. 9, ¶ 0093, lines 4-6, “protein concentrations between about 10 mg/mL and about 100 mg/mL”; Pg. 16, ¶ 0174, lines 1-6, “antibody therapeutics that can be formulated… [include] pembrolizumab”).
Pub. ‘925 further teaches pharmaceutical formulations of antibodies typically contain L-histidine buffer, sucrose, polysorbate 80, and methionine (Pg. 1, ¶ 0008, mentions L-histidine buffer, sucrose, and polysorbate 80; Pg. 27, ¶ 0302, line 5, “methionine”).
The disclosure of the Pub. ‘925 differs from the instant claim 1 in that it does not teach the pharmaceutical formulation of pembrolizumab with the exact excipient concentrations nor a coformulation with anti-CTLA4 antibody.
“In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” (MPEP 2144.05[I]). Please see above explanation of routine optimization of antibody formulation variables.
Therefore, any optimization of antibody formulation components would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the application would immediately envisage the claimed concentration range of 1-25 mg/mL of pembrolizumab from the disclosed range of 10-100 mg/mL as stated in Pub. ‘925, achieving the range without undue experimentation.
Pub. ‘119, WO ‘675, WO ‘413, and Pub. ‘925 are considered analogous to the present invention as they are all in the same field of antibody structure and formulation. It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the application to utilize anti-CTLA4 antibody comprising SEQ ID NOs: 48 and 88 and pembrolizumab in a pharmaceutical coformulation because:
Pub. ‘119 teaches a formulation of anti-CTLA4 antibody,
WO ‘675 teaches anti-CTLA4 antibody comprising SEQ ID NOs: 48 and 88,
teaches anti-CTLA4 antibody and pembrolizumab in a coformulation, and
Pub. ‘925 teaches pembrolizumab formulated with the same excipients as taught in Pub. ‘119.
The prior art includes each element prior to the effective filing date of the application, the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person having ordinary skill in the art prior to the effective filing date of the application would be motivated to combine anti-CTLA4 antibody (comprising SEQ ID NOs: 48 and 88 as taught in WO ‘675) and pembrolizumab together to improve therapeutic efficiency (treat bacterial infections as taught WO ‘413) in a formulation suitable for both antibodies (as taught in Pub. ‘119 and Pub. ‘925).
MPEP 2143(I)(A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950).”
Excipients are identical in formulations of both anti-CTLA4 antibody (Pub. ‘119) and pembrolizumab (Pub. ‘925), with Pub. ‘119 teaching the excipient concentrations (e.g. matching the claimed concentrations or a person having ordinary skill in the art arriving at the claimed concentrations through routine optimization), indicating a coformulation would be successful. A person having ordinary skill in the art would recognize the results of the combination were predictable and have a reasonable expectation of success.
Claims 2-6
Claims 2-6 recite coformulations with either specific ratios of pembrolizumab to anti-CTLA4 antibody or concentrations of the antibodies, including the following:
the ratio of the anti-PD1 antibody to the anti-CTLA4 antibody is 1:2, 1:1, 2:1, 10:1, 1:10, 8:3, or 8:1 w/w (see claims 2-3),
the concentration of the anti-CTLA4 antibody is about 1.25 mg/ml, 2.5 mg/ml, 2.9 mg/ml, 5 mg/ml, 7.9 mg/ml, 10 mg/ml, 12.5 mg/ml, 25 mg/ml. (see claims 4 and 6), and
the concentration of the anti-PD1 antibody is about 25 mg/mL, 22.7 mg/mL, 2.27 mg/mL, 21.1 mg/mL or 23.5 mg/ml (see claims 5-6).
As described above, Pub. ‘925 teaches a pharmaceutical formulation with about 10-100 mg/mL pembrolizumab (Pg. 9, ¶ 0093, lines 4-6, “protein concentrations between about 10 mg/mL and about 100 mg/mL”; Pg. 16, ¶ 0174, lines 1-6, “antibody therapeutics that can be formulated… [include] pembrolizumab”).
Pub. ‘119 further teaches a pharmaceutical formulation with about 0.1-100 mg/mL of anti-CTLA4 antibody (Pg. 6, ¶ 0060, line 3).
Using the concentration ranges for pembrolizumab and anti-CTLA4 antibody provided in Pub. ‘925 and Pub. ‘119 respectively, the following ratios of pembrolizumab:anti-CTLA4 antibody can be calculated: 1:2, 1:1, 2:1, 10:1, 1:10, 8:3, or 8:1 w/w (see below calculations, applicable to claims 2-3).
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While the exact claimed ratios and concentrations of pembrolizumab and anti-CTLA4 antibody are not explicitly stated in the prior art, they fall within the disclosed concentration ranges of Pub. ‘925 and Pub. ‘119 (i.e. 10-100 mg/mL of pembrolizumab and 0.1-100 mg/mL of anti-CTLA4 antibody). Antibody concentrations in a liquid formulation can be adjusted to contain “therapeutically effective amounts of these proteins in volumes useful for [subcutaneous] and [intramuscular] injections” (Pub. ‘925, Pg. 2, ¶ 0018, last 3 lines), wherein the therapeutically effective amounts “may be determined by standard techniques which are well within the craft of a skilled artisan, such as a physician” (Pub. ‘925, Pg. 6 ¶ 0058, last 3 lines). "[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).
It is a common objective in the art to optimize result effective variables (i.e. antibody concentrations, applicable to pembrolizumab and anti-CTLA antibody), so as to achieve optimal effect and maximal benefit (i.e. creating an antibody formulation with a therapeutically effective concentration suitable for injection). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of antibody concentrations would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the application would immediately envisage the claimed ratios and concentrations of pembrolizumab and anti-CTLA4 antibody a recited in claims 2-6 and achieve them without undue experimentation in order to create an antibody coformulation with therapeutically effective antibody concentrations suitable for injection.
Claim 7
Pub. ‘119 further teaches the inclusion aminopolycarboxylic acids, specifically EDTA and its derivative (Pg. 2, ¶ 0023).
DTPA is an aminopolycarboxylic acid and structural analog of EDTA.
While DTPA is not explicitly stated in Pub. ‘119, Zhou et al. teach both EDTA and DTPA are used interchangeably in antibody formulations (Pg. 4239, Abstract). Zhou et al. does not teach coformulations of anti-CTLA4 and pembrolizumab.
It is established that equivalents known for the same purpose can be substituted. Here, EDTA as taught in Pub. ’119 can be substituted for DTPA to serve the purpose of a chelating agent.
“In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art” (MPEP 2144.06).
Zhou et al. teach EDTA and DTPA are used interchangeably and Pub. ‘119 teaches inclusion of EDTA, both regarding antibody formulations. There is a reasonable expectation of success in the substitution of EDTA for DTPA because both EDTA and DTPA are chelators that reduce protein degradation.
It would be obvious to a person of ordinary skill in the art prior to the effective filing date of the instant application to substitute EDTA for DTPA if they desire is to use such agent in in a pharmaceutical formulation of protein(s).
Claims 8-9
Pub. ‘119 further teaches a liquid formulation in a glass vial (Pg. 32, ¶ 0360).
Claim 10
WO ’413 further teaches a method for treating bacterial infections in a human with formulations of anti-CTLA4 and pembrolizumab, some of which are chronic (Pg. 48, last ¶, penultimate line, “chronic bronchitis”).
Accordingly, Pub. ‘119 in view of WO ‘675, WO ‘413, Pub. ‘925, and Zhou et al., as evidenced by French and Robson, Bose and Sinha, and Ewert et al., make obvious instant claims 1-10.
Conclusion
Claims 1-10 are pending. Claims 1-10 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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