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 .
Election/Restrictions
Applicant’s election of Species A (i.e., breast cancer as a single and specific cancer); and Species B (i.e., an anti-PD(L)1:TGFβRII fusion protein comprising SEQ ID NO: 7 as the light chain and SEQ ID NO: 8 as the heavy chain as the single and specific PD-1 and TGFβ inhibitors, and niraparib as a single and specific PARP inhibitor) in the reply filed on April 2, 2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Status of Claims
Claims 1-15 were originally filed on May 2, 2023.
The amendment received on October 12, 2023, amended claims 1-15; and added new claims 16-18.
Claims 1-18 are currently pending and claims 1-9, 11-12, 14, and 16-17 are under consideration as claims 10, 13, 15, and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 2, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/080242 filed November 1, 2021, and claims priority under 119(e) to U.S. Provisional Application No. 63/108,630 filed on November 2, 2020.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 12, 2023; and April 2, 2026, are being considered by the examiner.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, with respect to “treating” a cancer, it is noted that the instant specification defines “treating” as referring to taking steps to obtain beneficial or desired results including clinical results (See instant, pg. 21, last paragraph). The instant specification further notes that “treating” includes prophylaxis as well as the alleviation of established symptoms of a condition (See instant, pg. 21, last paragraph). “Treating” a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms (See instant, pg. 21, last paragraph to pg. 22, 1st paragraph). As such, “treating” in claim 1 encompasses preventing or delaying the appearance of clinical symptoms of a cancer, inhibiting a cancer, relieving or attenuating a cancer, or prophylaxis/alleviation of established symptoms of a cancer. However, the instant specification does not define what constitutes “inhibiting” a cancer. Thus, the plain and ordinary meaning of the term applies. “Inhibit” is defined as relating to restrain or hinder; to prohibit, forbid; and/or to stop, prevent, or decrease the rate of (a chemical reaction) (“Inhibit”, Collins English Dictionary, available online at www.dictionary.com/browse/inhibit, 6 pages (accessed on 5/11/26) at pg. 2). “Prevent” is defined as relating to keep from happening or existing (See “Prevent”, Merriam-Webster, available online at www.merriam-webster.com/dictionary/prevent, 9 pages (accessed on 7/15/25) at pg. 1). As such, “inhibit” and “prevent” encompass 100% inhibition and 100% prevention. Thus, “treating” in claim 1 encompassing 100% inhibition of a cancer.
With respect to a PD-1 inhibitor, it is noted that the instant specification defines a PD-1 inhibitor as referring to a molecule that inhibitors the PD-1 pathway (See instant, pg. 17, last paragraph). The instant specification notes that inhibition in this context need not be complete or 100% (See instant, pg. 17, last paragraph). Instead, inhibition means reducing, decreasing, or abrogating binding between PD-1 and one or more of its ligands and/or reducing, decreasing or abrogating signaling through the PD-1 receptor (See instant, pg. 17, last paragraph). As such, the claimed “PD-1 inhibitor” encompasses any molecule, e.g., small molecule, protein, peptide, nucleic acid, saccharide, etc., that reduces, decreases, or abrogates binding between PD-1 and one or more of its ligands and/or reduces, decreases or abrogates signaling through the PD-1 receptor.
With respect to a TGF-beta inhibitor, it is noted that the instant specification defines a TGF-beta inhibitor as referring to a molecule that inhibits the TGF-beta pathway (See instant, pg. 20, last paragraph). The instant specification notes that inhibition in this context need not be complete or 100% (See instant, pg. 20, last paragraph). Instead, inhibition means reducing, decreasing, or abrogating binding between TGF-beta and the TGF-beta receptor and/or reducing, decreasing or abrogating signaling through the TGF-beta receptor (See instant, pg. 20, last paragraph). As such, the claimed “TGF-beta inhibitor” encompasses any molecule, e.g., small molecule, protein, peptide, nucleic acid, saccharide, etc., that reduces, decreases, or abrogates binding between TGF-beta and the TGF-beta receptor and/or reducing, decreasing or abrogating signaling through the TGF-beta receptor.
With respect to a PARP inhibitor, it is noted that the instant specification defines a PARP inhibitor as referring to a molecule that inhibits the PARP pathway (See instant, pg. 16, last paragraph). It includes inhibitors of any one of the over 15 different enzymes in the PARP family that engage in a variety of cellular functions including cell cycle regulation, transcription and repair of DNA damage (See instant, pg. 16, last paragraph). The PARP can be a small molecule (e.g., a small organic or inorganic molecule), a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin (See instant, pg. 16, last paragraph). The instant specification teaches that the PARP inhibitor is selected from the group consisting of ABT-767, AZD 2461, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib, IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, NU 1025, NU 1064, NU 1076, NU1085, ON02231, PD 128763, olaparib, rucaparib, R 503, R554, niraparib, SBP 101, SC 101914, simmiparib, talazoparib, veliparib, pamiparib, WW 46, 2-(4-(trifluoromethyl)phenyl)- 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, nicotinamide, theophylline and derivatives thereof (See instant, pg. 16, last paragraph).
Sequence Interpretation
For claim 3, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to each CDR amino acid sequence with any N- and/or C-terminal additions to each CDR sequence.
For claim 4, please note the Examiner is interpreting the scope as open-ended where the encompassed extracellular domain of TGFbeta-RII is the full length amino acid sequence, but a fragment of the full length extracellular domain encompasses any fragment size ranging from any dipeptide (i.e., any two contiguous amino acids) up to a fragment with a single deleted residue at the N- or C-terminus. It is noted that SEQ ID NO: 11 constitutes the full length TGFbeta-RII extracellular domain spanning residues 472-607 (i.e., 136 total amino acids) of instant SEQ ID NO: 8. SEQ ID NOs: 12-13 constitute fragments of the full length TGFbeta-RII extracellular domain where SEQ ID NO: 12 spans residues 491-607 of SEQ ID NO: 8, and SEQ ID NO: 13 spans residues 493-607 of SEQ ID NO: 8.
For claim 6, please note that the Examiner is interpreting the scope as open-ended requiring at least 90% identity to SEQ ID NOs: 7-8 (note: elected by Applicants) with any N- and/or C-terminal additions. It is noted that 90% of SEQ ID NO: 7 (i.e., 216 total amino acids) encompasses up to 21 amino acid modifications including substitutions, deletions, and/or insertions. Plus, it is noted that 90% of SEQ ID NO: 8 (i.e., 607 total amino acids) encompasses up to 60 amino acid modifications including substitutions, deletions, and/or insertions. However, as will be further articulated below, in light of the definition of percent identity in the specification, the number of conservative substitutions is not limited by the 90% identity limitation.
Claim Objections
Claims 1-9, 11-12, and 16-17 are objected to because of the following informalities: the claims recite, “PD-1 inhibitor”, “TGFβ inhibitor”, and/or “PARP inhibitor”. Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses “programmed death-1 (PD-1)”, “transforming growth factor beta (TGFβ)”, and/or “poly ADP ribose polymerase (PARP)” for the first recitation, thereafter the abbreviations may be utilized. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- Written Description
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 Rejections - 35 USC § 112
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 4 is 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Dependent claim 4 includes where the TGFbeta inhibitor is an extracellular domain of TGFbeta-RII or a fragment thereof. The interpretation of this phrase is described above in the “Sequence Interpretation” section where the fragment encompasses any fragment ranging from any dipeptide (i.e., any two contiguous amino acids) up to a fragment with one deleted residue at the N- or C-terminus. In addition to certain manipulations of the full length extracellular domain of TGFbeta-RII (i.e., instant SEQ ID NO: 11), the fragment must also be “capable of binding TGFbeta”. Thus, the scope of claim 4 encompasses where the TGFbeta inhibitor is a fragment of the full length TGFbeta-RII extracellular domain, which is 136 total amino acids, thereby encompassing a large array of fragments without any structure-function correlation established. Therefore, the claimed TGFbeta inhibitor of claim 4 encompasses fragments without a core sequence necessary for the fragment to exhibit the require function of being capable of binding TGFbeta.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Bedi et al. WO 2021/007428 A2 teaches that the TGFbeta-R extracellular domain can be selected from SEQ ID NOs: 177-180 (See Bedi, [00056], [000187]). However, Bedi et al. does teach any fragments of SEQ ID NOs: 177-180 that would exhibit the function of binding to TGFbeta. Thus, the claim is directed to fragments with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches two fragments of SEQ ID NO: 11; namely, SEQ ID NOs: 12-13 (See instant, pg. 93). SEQ ID NO: 12 represents residues 491-607 of instant SEQ ID NO: 8 (i.e., 117 total amino acids), and SEQ ID NO: 13 represents residues 493-607 of instant SEQ ID NO: 8 (i.e., 115 total amino acids). The specification also teaches that the N-terminal 26 or less amino acids of SEQ ID NO: 11 can be deleted, such as 14-21 or 14-26 N-terminal amino acids (See instant, pg. 25, last paragraph). However, there is no indication of a necessary core sequence that each TGFbeta-RII sequence must have to be capable of binding TGFbeta. Nor do SEQ ID NOs: 12-13 constitute a representative number of species that fall within the claimed genus of fragments. Thus, the is not sufficient for the skilled artisan to envisage which TGFbeta-RII fragments will preserve the claimed function other than SEQ ID NOs: 12-13.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claim 4 does not meet the written description requirement.
Claim 6 is 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.
Instant claim 6 is drawn to the anti-PD(L)1:TGFβRII fusion protein of claim 5 and further limits the light chain sequence and the heavy chain sequence of the fusion protein to having “at least 90% sequence identity” to the light and heavy chain sequences recited. The claim is drawn to a genus of fusion proteins, specifically those with at least 90% identity to the recited sequences, which are limited by the functional limitations of being a PD-1 inhibitor and a TGFβ inhibitor and capable of treating cancer when used in the claimed method.
Additionally, the instant disclosure defines “Percent (%) sequence identity” as “the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity” (page 18, last paragraph to pg. 19, 1st paragraph). Such a definition, which does not include conservative substitutions in the % identity calculations, demonstrates that the breadth of the genus and allows for modifications above 10%, so long as they are conservative.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the claimed functions, nor does the disclosure identify a structure function relationship that would allow an ordinarily skilled artisan to reasonably identify which species of the claim would perform the claimed function(s).
The examples of the disclosure used the fusion protein bintrafusp alfa, which is disclosed as having light and heavy chain sequences of instant SEQ ID NOs: 7 and 8, respectively. The disclosure also teaches a light chain sequence of SEQ ID NO: 15 with heavy chains of SEQ ID NO: 17 or 18 (pages 93-94).
These fusion proteins, comprising the heavy and light chain sequences identified in the disclosure, with 100% sequence identity, particularly in the CDRs of the PD-(L)1 antibody, represent the species of the instantly claimed invention that applicant was in possession of at the time of the effective filing date.
It is noted that the instant disclosure also identifies various other anti-PD(L)1:TGFβRII fusion proteins that can be used in the claimed methods (page 28, last paragraph – page 29, 1st paragraph); however, it is not apparent that any of the light and heavy chain sequence pairs recited are additional species of the claimed invention having at least 90% sequence identity to the light and heavy chain sequences of (1), (2), or (3) as recited in the instant claim.
For instance, the instant claim encompasses fusion proteins comprising combinations which include light chain sequences that are at least 90% identical to either SEQ ID NOs: 7 or 15. The disclosure also teaches light chains from the reference WO 2020/014285 including WO’285, SEQ ID NOs: 15 and 296; however, these are not species of the instantly claimed invention. For instance, instant SEQ ID NO: 7 and WO’285 SEQ ID NO: 15, have 39.2% sequence identity (with 95/214 matching AA) and instant SEQ ID NO: 7 and WO’285, SEQ ID NO: 296 have 37.5% sequence identity (with 93/218 matching AA). Similarly, instant SEQ ID NO: 15 and WO’285, SEQ ID NO: 15 have 83.5% sequence identity (with 184/214 matching AAs) and instant SEQ ID NO: 15 and WO’285, SEQ ID NO: 296 have 85.4% sequence identity (with 187/218 matching AAs). Comparisons which demonstrate that the light chain sequences disclosed on page 33-34 are not species of the instant claims as they do not have at least 90% sequence identity to one of the instantly recited light and heavy chain sequence groups.
The disclosure does not provide a representative number of species of the claimed genus performing the claimed functions. Furthermore, the disclosure does not provide a structure-function relationship that would allow one of ordinary skill in the art to predictably identify which species of the claimed genus would perform the claimed functions, particularly in absence of a full complement of 6 CDRs with 100% identity in the anti-PD(L)-1 antibody of the fusion protein.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a predictable structure function relationship between fusion protein/antibody structure and function. Rather, the art suggests that, particularly for antibodies, binding depends on the full complement of 6 CDRs (3 from the heavy chain and 3 from the light chain) with 100% identity.
For example, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs in the anti-PD(1) antibody.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses similar challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding to PD(L)1.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even years after the effective filing date of the claimed invention even modifications using conservative substitution were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of fusion proteins that are encompassed by the instant the claim. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functional which would allow for the predictable modification of the claimed sequences, particularly in the CDRs, while maintaining the claimed binding function/treatment of cancer. Therefore, the instant claim was found to not meet the written description requirement.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Claims 1-9, 11-12, 14, and 16-17 are 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 treating cancer by administering to a subject a PD-1, TGFbeta inhibitor and a PARP inhibitor where treating does not encompass 100% prevention, prophylaxis or inhibition, does not reasonably provide enablement for treating any cancer by administering to a subject a PD-1, TGFbeta inhibitor and a PARP inhibitor where treating encompasses 100% prevention, prophylaxis or inhibition.
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 Wriqht, 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 Cortriqht, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The eight In re Wands factors are applied to Claims 1-9, 11-12, 14, and 16-17 as follows:
The Breadth of the Claims and The Nature of the Invention
Although addressing that the subject is at risk of suffering from cancer in claim 1 by administering a PD-1 inhibitor, a TGFbeta inhibitor, and a PARP inhibitor (hereinafter referred to as “the combination”), Applicants do not provide any evidence in the specification that the combination can 100% prevent/inhibit or prophylactically treat any type of cancer. It is noted that the instant specification does not define what is meant by inhibition or prevention of cancer. As such, the plain and ordinary meaning of the words applies. Please see the “Claim Interpretation” section supra, for further details of the scope and breadth of the claimed invention as it encompasses 100% inhibition, 100% prevention, and prophylactic cancer treatment. Thus, the claimed invention encompasses where 100% prevention, 100% inhibition, and treatment prior to cancer manifestation. Accordingly, claims 1-9, 11-12, 14, and 16-17 are unduly broad with respect to preventing/inhibiting and/or prophylactically treating any type of cancer by administering the combination.
The State of the Prior Art
Although 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 preventing/inhibiting and/or prophylactically treating cancer broadly is underdeveloped. In particular, there is there a known anticancer agent that prevents any type of cancer. Therefore, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e., administering the combination to a healthy subject or one susceptible to in hopes of preventing cancer), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work. As such, the cancer prevention and prophylactic treatment involves a very high level of unpredictability.
Chattopadhyay et al. teaches that despite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level (See Chattopadhyay et al., Scientific Rep. 15:20334 (2025) at abstract). This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (e.g. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems (See Chattopadhyay, abstract). We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft model systems from multiple cancer types, and in-vitro culture that certain conditions increase stochasticity of the clonal landscape of cancer growth (See Chattopadhyay, abstract). Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable (See Chattopadhyay, abstract). Therefore, the level of predictability in the art with respect to 100% prevention/inhibition and/or prophylactic treatment of any cancer remains high.
The Level of Skill in the Art
Practitioners in this art (medical clinicians, pharmacists, doctors and/or pharmaceutical chemists) would presumably be highly skilled in the art for the 100% prevention/inhibition and/or prophylactic treatment of cancer.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable. If one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e., administering the combination to a subject at risk of suffering from cancer), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work.
In the instant case, Applicants do not demonstrate that any combination administered to a subject at risk of suffering from cancer is an effective therapy. Rather, Applicants rely on experimental animal models demonstrating where the combination treated cancer by reducing the tumor volume (See instant, Example 1; Figures 3-8). Thus, Applicants appear to rely on the assumption that by providing evidence that the claimed combination reduces tumor volume in animal models would prevent or prophylactically treat any cancer in a subject. However, such an assumption cannot be made because there is no indication that administering the combination to subjects at risk of developing any type of cancer would function as intended.
Furthermore, with specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] ...anti-cancer treatment." In re Application of Hozumi et al, 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, given highly unpredictable nature of prevention and/or prophylactic treatment of cancer broadly and given that the Specification fails to demonstrate any data or evidence that the claimed combination prevents any type of cancer and/or prophylactically treats cancer, there would be no way of determining without undue experimentation whether the claimed combination exhibits such a desired result. Without more experimentation demonstrating the efficacy of a representative number of claimed combinations, the level of unpredictability remains high. Therefore, it is unpredictable that the claimed combination will 100% prevent/inhibit any type of cancer and/or prophylactically treat cancer in a subject.
The Amount of Direction Provided by the Inventor,
The Presence or Absence of Working Examples, and
The Quantity of Experimentation Necessary
The specification does not enable any person skilled in the art to which it pertains (i.e. administering the combination to a subject at risk of suffering from cancer) to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual 100% prevention/inhibition of any cancer and/or prophylactic treatment of any cancer by administering to a subject the combination. Applicants fail to provide the guidance and information required to ascertain whether the claimed combination will be effective against 100% preventing/inhibiting any type of cancer and/or prophylactically treating any cancer without resorting to undue experimentation. Applicant's limited disclosure is noted but is not sufficient to justify claiming prevention and prophylactic treatment of all cancers broadly.
Absent a reasonable a priori expectation of success for using the combination to 100% prevent/inhibit any type of cancer and/or prophylactically treat any type of cancer, one skilled in the art would have to extensively test many various tumor types. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise. The amount of direction or guidance presented in the specification is limited to the treatment of cancer in specific animal models where treatment results in reduction of tumor volume (See instant, Example 1; Figures 3-8). In the absence of such information, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1-9, 11-12, 14, and 16-17, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in claims 1-9, 11-12, 14, and 16-17 would not be enabled by the written disclosure for the 100% prevention/inhibition or prophylactic treatment of any cancer.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-7, 9, 11-12, 14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bedi et al., WO 2021/007428 A2 published on January 14, 2021 (effective filing date of July 9, 2019), Spira et al., Cancer Res 80(Supplement):P3-09-06 (February 2020), Vinayak et al., JAMA Oncol. 5:1132-1140 (2019), alone or as evidenced by, American Medical Association, “Bintrafusp alfa”, available online at https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/bintrafusp-alfa.pdf, 1 pages (2020).
For claims 1-7, 9, 11-12, 14 and 16-17, Bedi et al. claims a method of treating a subject having a neoplastic disease or cancer by administering a fusion protein comprising an antibody and one or more ligand traps (ALT) where a ligand trap is a ligand-binding sequence of a receptor extracellular domain or fragment thereof can be TGFbeta in combination with another agent (See Bedi, claims 1, 29, 32-33, 108, 118, 141). The antibody of the can specifically bind one or more of PD1, PD-L1, or PD-L2 where the antibody binds an disables PD-L1 or PD1 (See Bedi, claims 17-18, 43-44, 113-116) thereby constituting a PD1 inhibitor. The fusion protein can inhibit the interaction of TGFbeta and TGFbeta-RII (See Bedi, claim 28). In a specific embodiment, Bedi et al. teaches a method of treating a subject having cancer by administering an agent that blocks VEGF signaling in combination with an agent that blocks TGFbeta signaling wherein at least one of VEGF and TGFbeta are inhibited in the tumor microenvironment (See Bedi, claim 175). The TGFbeta-blocking agent (i.e., inhibitor) is a tumor-targeted ALT where the ligand trap of the ALT comprising a ligand-binding sequence of TGFbeta-RII extracellular domain, and more specifically, the ALT is M7824 (bintrafusp alfa) (i.e., the ALT comprises an antibody that binds PD-L1 fused to a ligand-binding sequence of TGFbeta-RII extracellular domain) (See Bedi, claim 176, 179 and 181-182; specification, [000629]-[000631]). Bedi et al. does not expressly teach the amino acid sequence of M7824 (i.e., bintrafusp alfa). However, as evidenced by the American Medical Association, the amino acid sequence of the heavy chain (note: contains the TGFbeta-RII extracellular domain that is 100% identical to instant SEQ ID NOs: 11-13) of M7824 is 100% identical to instant SEQ ID NO: 8 thereby corresponding to 100% identity to instant CDR amino acid sequences of instant SEQ ID NOs: 1-3, and the amino acid sequence of the light chain of M7824 is 100% identical to instant SEQ ID NO: 7 thereby corresponding to 100% identity to instant CDR amino acid sequences of instant SEQ ID NOs: 4-6. Furthermore, in Example 2, Bedi et al. demonstrates that administering 5 mg/kg i.p. q 6d of a fusion protein comprising anti-PDL1 fused to TGFbeta-RII extracellular domain or comprising anti-PDL1 fused to TGFbeta-RII extracellular domain fused to BTLA extracellular domain inhibited pancreatic tumor growth compared to control (See Bedi, [000639]; Figure 5C; Example 2). Plus, Bedi et al. teaches that the cancers to be treated include pancreatic and breast cancer (See Bedi, [000580]). As demonstrated by Spira et al., M7824 demonstrated efficacy in a cohort of subjects suffering from triple negative breast cancer (See Spira, pg. 1-2: Results and Conclusions). Thus, the combined teachings of Bedi et al. and Spira et al. suggest where M7824 can treat a subject suffering from pancreatic or triple negative breast cancer. Therefore, the method of treating cancer such as pancreatic or triple negative breast cancer taught by Bedi suggests administering a fusion protein of a PD-1 inhibitor and a TGFbeta inhibitor; more specifically, an anti-PD(L)1:TGFbeta-RII fusion protein, to a subject in need thereof where this fusion protein reads on the instant PD-1 and TGFbeta inhibitors as recited in instant claims 1-7, 14, and 16.
Moreover, Bedi et al. claims where the “another agent” is a chemotherapeutic agent, hormonal agent, PARP inhibitor, DNA-repair inhibitor, ionizing radiation or CDK4/6 inhibitor (See Bedi, claim 139). Specific species of PARP inhibitors taught by Bedi et al. are niraparib, Olaparib, and rucaparib (See Bedi, [000585]). As such, since Bedi et al. teaches niraparib as a PARP inhibitor and niraparib is a species of a small molecule PARP inhibitor, it would necessarily follow that Bedi et al. teaches where the PARP inhibitor is a small molecule. Furthermore, Vinayak et al. teaches that administration of 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab (i.e., an anti-PD1 antibody) on day 1 of each 21-day cycle to a subject with advanced triple negative breast cancer resulted in numerically high response rates providing a promising antitumor therapy (See Vinayak, abstract). As such, niraparib administered orally at a dose of 200 mg QD (i.e., once a day) when combined with a PD-1 inhibitor is known to treat triple negative breast cancer in a subject. Therefore, when considering the teachings of Bedi et al. as a whole, the method of treating cancer such as pancreatic or triple negative breast cancer taught by Bedi suggests administering an ALT such as M7824 in combination with another agent such as a PARP inhibitor such as niraparib as recited in instant claims 1, 9, 11-12, 14, and 17.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing data of the instant application to modify the teachings of Bedi et al. and administer M7824 as a fusion protein comprising a PD-L1 antibody inhibitor fused to a TGFbeta-RII extracellular domain inhibitor in combination with niraparib as a PARP inhibitor to a subject in order to treat pancreatic or triple negative breast cancer in a subject. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because M7824 was known to demonstrate efficacy in patients suffering from triple negative breast cancer as taught by Spira et al.; and because a combination of oral 200 mg QD niraparib and pembrolizumab as a PD-1 inhibitor was known to treat patients suffering from triple negative breast cancer as taught by Vinayak et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a combination of a fusion protein comprising an antibody and one or more ligand traps (ALT) where a ligand trap is a ligand-binding sequence of a receptor extracellular domain or fragment thereof with another agent of Bedi et al. was administered to a subject in order to treat a cancer such as pancreatic or breast cancer, and therefore, substituting M7824 as the fusion protein comprising an antibody PD-L1 inhibitor fused to a TGFbeta-RII extracellular domain inhibitor and substituting oral 200 mg QD niraparib as the another agent would support the treatment of pancreatic cancer or triple negative breast cancer in a subject by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the simple substitution of one known element for another to obtain predictable results pursuant to KSR.
With respect to the dosage of niraparib, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed dosage range of niraparib would have been obvious to one of ordinary skill in the art since the prior art dosage (i.e., 200 mg QD) lies within with the claimed dosage range of niraparib (i.e., 0.1 to 1000 mg QD).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Bedi et al., WO 2021/007428 A2 published on January 14, 2021 (effective filing date of July 9, 2019) and Vugmeyster et al., Clin. Pharmacol. & Ther. 108:566-574 (first available March 2020), alone or as evidenced by, American Medical Association, “Bintrafusp alfa”, available online at https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/bintrafusp-alfa.pdf, 1 pages (2020).
For the limitations of claim 8 that are incorporated from claims 1 and 5-7, please see discussion of Bedi et al. and the American Medical Association supra.
For claim 8, with respect to where M7824 is administered intravenously at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W:
As discussed supra, in Example 2, Bedi et al. teaches administering 5 mg/kg i.p. q 6d of a fusion protein comprising anti-PDL1 fused to TGFbeta-RII extracellular domain to a subject suffering from pancreatic cancer. Bedi et al. also teaches that the fusion protein can be administered intravenously (See Bedi, [000581], [000590]). Thus, Bedi et al. satisfies the claim limitation with respect to where M7824 is administered intravenously. However, Bedi et al. does not expressly teach where M7824 is administered at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W.
Vugmeyster et al. teaches that bintrafusp alfa showed a manageable safety profile and clinical activity in phase I studies in patients with heavily pretreated advanced solid tumors (See Vugmeyster, abstract). The recommended phase 2 dose (RP2D) was selected based on integration of modeling, simulations, and all available data (See Vugmeyster, abstract). A 1,200-mg every 2 weeks (q2w) dose was predicted to maintain serum trough concentration (Ctrough) that inhibits all targets of bintrafusp alfa in circulation in > 95% of patients, and a 2,400-mg every 3 weeks (q3w) dose was predicted to have similar Ctrough (See Vugmeyster, abstract). A trend toward an association between exposure and efficacy variables and a relatively stronger inverse association between clearance and efficacy variables were observed (See Vugmeyster, abstract). Exposure was either weakly or not correlated with probability of adverse events. The selected intravenous RP2D of bintrafusp alfa is 1,200 mg q2w or 2,400 mg q3w (See Vugmeyster, abstract). Thus, the teachings of Vugmeyster et al. suggest administering M7824 at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing data of the instant application to modify the teachings of Bedi et al. and administer M7824 intravenously at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W in combination with niraparib as a PARP inhibitor to a subject in order to treat cancer in a subject. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because M7824 was known to show a manageable safety profile and clinical activity when administered at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W as taught by Vugmeyster et al.. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that a combination of a fusion protein comprising an antibody and one or more ligand traps (ALT) where a ligand trap is a ligand-binding sequence of a receptor extracellular domain or fragment thereof with another agent of Bedi et al. was administered to a subject in order to treat a cancer where the ALT was known to be administered intravenously, and therefore, substituting M7824 as the fusion protein comprising an antibody PD-L1 inhibitor fused to a TGFbeta-RII extracellular domain inhibitor to be administered intravenously at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W and substituting niraparib as the another agent would support the treatment of cancer in a subject by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of a known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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