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 3, 5, 8-9, 11-12, 15, 21, 23, 26-27, 29, 31, and 40-43 are cancelled. Claims 1-2, 4, 6-7, 10, 13-14, 16-20, 22, 24-25, 28, 30, 32-39, and 44-47 are pending.
Claims 6, 10, 13, 16, 28, 30, 33, 45, and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 08/06/2026.
Claims 1-2, 4, 7, 14, 17-20, 22, 24-25, 32, 34-39, 44, and 46 are currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/US22/34834 (filed on 06/24/2022) which claims benefit of Provisional U.S. Application Nos. 63/215,260 (filed on 06/25/2021) and 63/353,223 (filed on 06/17/2022). 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 1-2, 4, 7, 14, 17-20, 22, 24-25, 32, 34-39, 44, and 46 have an effective filing date of 06/25/2021 corresponding to Provisional U.S. Application No. 63/215,260.
Information Disclosure Statement
The information disclosure statement(s) filed on 12/18/2023 and 01/19/2024 has/have been considered. Signed copies are enclosed. All references considered unless marked with strikethrough.
Notably, the disclosure statement filed on 01/19/2024 lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Objections
Claims 1-2, 4, 14, 17-18, 22, 24, 38, 44, and 46 are objected to because of the following informalities:
Claims 1, 44, and 46: “TrIgGering” should be replaced with Triggering”.
Claim 2: “SEQ ID NOS:” in part (b) and “SEQ ID NO” in part (c) should be replaced with “SEQ ID NO:”.
Claim 4, 17-18, 22, and 24: “antigen-binding protein” (multiple instances throughout claim set) should be replaced with “antigen binding protein” for consistency.
Claim 14: “a light chain variable domain of SEQ ID NO: 201” in part (x) should be replaced with “a light chain variable domain sequence of SEQ ID NO: 201”.
Claim 38: “cholesterylester transfer protein” should be replaced with “cholesteryl ester transfer protein”.
Claim 38: “SGL2” should be replaced with “SGLT2”.
Claim 38: “Growth Differential Factor 15” should be replaced with “Growth Differentiation Factor 15”.
Claim 38: “I(f) current Inhibitor” should be replaced with “I(f) current inhibitor”.
Claim 46: subscripts should be used for all numbers after variable amino acid residues in part (b)(ii).
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.
Claims 1-2, 7, 17-20, 22, 24-25, 32, 34-39, 44, and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
(A) Insufficient evidence of possession of invention regarding structure or other physical and/or chemical properties
Claim 1 is drawn to “[a] method of treating cardiovascular disease comprising administering to a subject in need thereof a therapeutically effective amount of an antigen binding protein that binds to TrigGering Receptor Expressed on Myeloid cells 1 (TREM-1); the antigen binding protein comprising” (lines 1-4) various amino acid sequences for light chain CDRs 1-3 and heavy chain CDRs 1-3. This recitation leads to 12,960,000 unique CDR combinations (15 LCDR1s x 15 LCDR2s x 15 LCDR3s x 15 HCDR1s x 16 HCDR2s x 16 HCDR3s = 12,960,000 unique CDR combinations). Claim 2 narrows the number of unique CDR combinations to 100,842 (7 LCDR1s x 7 LCDR2s x 7 LCDR3s x 7 HCDR1s x 7 HCDR2s x 6 HCDR3s = 100,842 unique CDR combinations). Thus, this language encompasses a large number of CDR combinations.
Claim 7 is drawn to the antigen binding protein wherein the light and heavy chain variable domains have at least 80% sequence identity to the recited amino acid sequences. Similarly, claim 25 is drawn to the antigen binding protein wherein the light and heavy chain have at least 90% sequence identity to the recited amino acid sequences. This language permits mutations to the framework region of (i) the light and heavy variable domains (claim 7) and (ii) the light and heavy chains of the antigen binding protein (claim 25). Furthermore, claim 7 specifies the light and heavy variable domains of the antigen binding protein comprise “a sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a nucleic acid sequence” (lines 11-13), indicating various SEQ ID NOs. The specification does not define moderately stringent conditions. Therefore, this recitation encompasses numerous polynucleotide sequences encoding the light and heavy variable domains of the antigen binding protein that satisfy the hybridization limitation.
Claim 17 is drawn to “one or more heavy chain framework amino acids of the anti-antigen-binding protein are replaced with corresponding amino acid(s) from another human antibody amino acid sequence” (lines 1-3). Claim 18 recites the same limitation regarding substitutions to the light chain framework amino acids. This language allows any mutation to the framework region, including replacing it entirely. Carter et al. (Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4285-9) teaches grafting CDR sequences from a murine antibody into human framework regions reduced affinity 80-fold (Pg. 4288, column 1, entire ¶ 2), indicating swapping framework regions can negatively impact antigen binding significantly despite retention of CDR sequences.
Claim 19 is drawn to the antigen binding protein “wherein the heavy chain comprises a constant region selected from heavy chain constant regions of an IgG, IgM, IgA, IgD, IgE, fragments thereof, combinations thereof, and modifications thereof in which one to ten heavy chain framework amino acids are replaced with corresponding amino acid(s) from another human antibody amino acid sequence” (lines 1-5). This language allows any 10 mutations to the heavy chain constant regions of an IgG, IgM, IgA, IgD, or IgE. Additionally, the language includes numerous combinations and fragments of the heavy chain constant regions.
Claims 44 and 46 are drawn to the antigen binding protein comprising light chain CDRs 1-3 and heavy chain CDRs 1-3 with numerous variable amino acid residues. For example, SEQ ID NO: 554 for light chain CDR2 in claim 44 comprises 7 variable amino acid residues, leading to 3,600 unique amino acid sequences for light chain CDR2 (3 X1s x 2 X2s x 3 X3s x 5 X4s x 4 X5s x 2 X6s x 5 X7s = 3,600 unique amino acid sequences). This issue is only further exacerbated when the other 5 CDRs are taken into account, which present similar variation. Thus, this language encompasses a large number of CDR sequences.
The instant specification states “’antigen binding protein’ refers to a polypeptide that is capable of specifically binding an antigen, e.g. a target or its signaling partner, or that is capable of binding an antigen with a measurable binding affinity” (¶ 0076). This definition includes multiple types of antigen binding proteins, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 4-5). In addition, antibody fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antigen binding proteins encompass a variety of species, each with their own advantages and disadvantages.
Thus, as instantly claimed, the claims read on a genus of variants of antigen binding proteins that bind TREM-1 comprising:
numerous combinations of CDRs (claims 1-2),
light and heavy variable domains with up to 20% variation (claim 7);
numerous polynucleotide sequences encoding the light and heavy variable domains of the antigen binding protein that satisfy the hybridization requirements (claim 7);
light and heavy chains with up to 10% variation (claim 25);
any mutation to the framework region of the light and heavy chains, including altering their sequences entirely (claims 17-18);
any 10 mutations to the heavy chain constant regions of an IgG, IgM, IgA, IgD, or IgE, including combinations and fragments thereof (claim 19); and
CDR sequences with numerous variable amino acid residues (claims 44 and 46).
Tables 7-10 of the instant specification delineate the amino acid and nucleotide sequences of (i) the heavy and light chains (Table 7, ¶ 0239), (ii) the light and heavy chain variable domains (Table 8, ¶ 0240), (iii) the light chain CDRs 1-3 (Table 9, ¶ 0241), and (iv) the heavy chain CDRs 1-3 (Table 10, ¶ 0242) for 15 distinct anti-TREM-1 antibodies. These 15 antibodies are identical to the recitations in claim 4 for the 6 CDR sequences and claim 14 for the light and heavy chain variable domains. Therefore, the instant specification teaches antigen binding proteins that bind TREM-1 in Tables 7-10 of the instant specification as specified in claims 4 and 14. The instant specification does not establish possession of the genus of variants of antigen binding proteins that bind TREM-1 as recited in the instant claims 1-2, 7, 17-19, 25, 44, and 46 nor does it suggest or disclose that all members of said genus would retain their ability to bind TREM-1.
As instantly claimed, the antigen binding protein can comprise numerous CDR combinations (claims 1-2), numerous variable amino acid residues (claims 44 and 46), up 20% variation in the light and heavy variable domains (claim 7), up to 10% variation in the light and heavy chains (claim 25), and any mutations to the framework region of the light and heavy chains (claims 17-18). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen-binding region of the antibody, i.e. anywhere in the VH and VL including the framework region, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicate amino acid substitutions within CDRs and framework regions can completely change the antigen recognition of the antibody; this problem would be further exacerbated when replacing entire CDRs.
In addition, as instantly claimed, the antigen binding protein can comprise any 10 mutations to the heavy chain constant regions of an IgG, IgM, IgA, IgD, or IgE, including combinations and fragments thereof (claim 19). Vafa et al. (An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations, Methods, Volume 65, Issue 1, 2014, Pages 114-126) teach a single amino acid substitution to an Fc domain can cause repositioning of key residues responsible for interacting with FcγRs, resulting in loss of function (Pg. 124, column 1, entire ¶ 2). This teaching indicates amino acid substitutions within Fc domains can inhibit their interactions with their receptors and lead to loss of function. This issue would be compounded when combinations and fragments of heavy chain constant regions (Fcs) are taken into account.
Finally, as instantly claimed, the antigen binding protein can comprise numerous polynucleotide sequences encoding the light and heavy variable domains of the antigen binding protein that satisfy the hybridization requirements (claim 7). Alberts et al. (Molecular Biology of the Cell, 4th edition, New York: Garland Science, 2002, Isolating, Cloning, and Sequencing DNA) teaches “[d]ifferent hybridization conditions allow less than perfect DNA matching” (Pg. 5, legend of Fig. 8-25). This teaching indicates the polynucleotide sequences can contain mutations as hybridization can produce mismatches. Those of ordinary skill in the art would not be able to identify without further testing which of those nucleic acids that hybridize as recited would also encode a polypeptide that binds to TREM-1.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”. The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004).
The instant specification fails to provide sufficient descriptive information in the broadly claimed genus of variants of antigen binding proteins that bind TREM-1 as recited in the claims 1-2, 7, 17-19, 25, 44, and 46. The instant specification does not provide specific or detailed structural characteristics of antigen binding protein variants that bind TREM-1 comprising:
numerous combinations of CDRs (claims 1-2),
light and heavy variable domains with up to 20% variation (claim 7);
numerous polynucleotide sequences encoding the light and heavy variable domains of the antigen binding protein that satisfy the hybridization requirements (claim 7);
light and heavy chains with up to 10% variation (claim 25);
any mutation to the framework region of the light and heavy chains, including altering their sequences entirely (claims 17-18);
any 10 mutations to the heavy chain constant regions of an IgG, IgM, IgA, IgD, or IgE, including combinations and fragments thereof (claim 19); and
CDR sequences with numerous variable amino acid residues (claims 44 and 46).
Furthermore, the instant specification does not demonstrate the functions of said variants are retained. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided: The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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, whatever is now claimed.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these variants could perform the same function (i.e. binding to TREM-1) as the sequences for the protein as recited in claims 1-2, 7, 17-19, 25, 44, and 46. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of protein variants having the functions listed in the claims based on the limited examples given in the instant specification (i.e. 15 distinct anti-TREM-1 antibodies as recited in Tables 7-10 and claims 4 and 14).
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, whatever 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(s) and functional attribute(s) of the encompassed genus of variants of the protein as claimed, 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, only the antigen binding proteins that bind TREM-1 in Tables 7-10 of the instant specification as specified in claims 4 and 14, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. §112, first paragraph.
(B) Insufficient evidence of possession of invention regarding functional characteristics coupled with a known or disclosed correlation between function and structure
Claim 20 is drawn to ”[a] method of treating cardiovascular disease comprising administering to a subject in need thereof a therapeutically effective amount of an antigen binding protein that competes for binding to TREM-1 with an antigen binding protein of claim 1” (lines 1-3). This recitation is functional language wherein the antigen binding protein that competes for binding to TREM-1 comprises a broad genus of structurally distinct antigen binding proteins.
The instant specification states “’antigen binding protein’ refers to a polypeptide that is capable of specifically binding an antigen, e.g. a target or its signaling partner, or that is capable of binding an antigen with a measurable binding affinity” (¶ 0076). The definition for antigen binding protein is incredibly broad and does not specify the minimum number of CDRs for binding i.e. they can contain less than 6 CDRs. As discussed above, Sifniotis et al. teach antigen binding proteins encompass a variety of distinct polypeptides (e.g. Fabs, scFvs, VHHs, and full-length antibodies) with different structures and functions. Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antigen binding proteins compete for binding to TREM-1 is not a sufficient description.
As such, claim 20 is drawn to a method of treating a cardiovascular disease comprising administering to a subject a genus of antigen binding proteins that compete for binding to TREM-1 with the antigen binding protein of claim 1. The instant specification fails to teach such a protein, indicating its existence is merely “contemplated” (¶ 0038).
Applicant is claiming a large and structurally diverse genus of antigen binding proteins that compete for binding to TREM-1 with the antigen binding protein of claim 1. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically the structures of the antigen binding proteins that compete for binding to TREM-1 with the antigen binding protein of claim 1. Applicant uses functional language to define the genus which is not sufficient as detailed above (see Sevy and Meiler for information regarding the difficulty in predicting structure from function alone).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has not disclosed a species within the genus claimed. Given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the lack of disclosure of species cannot sufficiently be representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences that confer upon an antibody the ability to compete for binding to TREM-1. It is well known in the art that antibodies generally comprise six parental CDRs. Absent a description of the at least minimal structural features correlating with a functional ability to compete for binding to TREM-1 which are shared by members of a genus of antigen binding proteins, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish what portion of an antigen binding protein (i.e. the CDRs) that confer the ability to compete for binding to TREM-1.
Although screening techniques can be used to find antigen binding proteins that possess the ability to compete for binding to TREM-1, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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, whatever is now claimed.”
Accordingly, given the difficulty associated with predicting structures of antigen binding proteins that compete for binding to TREM-1 with the antigen binding protein of claim 1 and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of claims 1-2, 7, 17-20, 25, 44, and 46. Claim 1-2, 7, 17-20, 25, 44, and 46 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Claims 22, 24, 32, and 34-39 are included in this rejection as they incorporate and/or depend on claim 1.
It is noted that claim 4 teaches the 6 CDR sequences and claim 14 teaches the light and heavy chain variable domains of the antigen binding protein that binds TREM-1, which are supported by the disclosure of 15 distinct anti-TREM-1 antibodies in the instant specification (see Tables 7-10, ¶ 0239-0242). These teachings are sufficient structural detail and comply with the written description requirements. Therefore, claims 4 and 14 will not be included in this rejection.
Claims 1-2, 4, 7, 14, 17-20, 22, 24-25, 32, 34-39, 44, and 46 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 a method of reducing one or more symptoms of atherosclerosis or myocardial infarction comprising administering to a subject in need thereof a therapeutically effective amount of an antigen binding protein that binds TREM-1 as recited in Tables 7-10, does not reasonably provide enablement for a method of treating all cardiovascular disease comprising administering to a subject in need thereof a therapeutically effective amount of a genus of antigen binding proteins that binds to TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding. 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 of the invention
The invention is drawn to a method of treating various cardiovascular diseases comprising administering to a subject in need thereof a therapeutically effective amount of a genus of antigen binding proteins that bind TREM-1, subject matter that is highly complex and unpredictable.
The invention involves complex and unpredictable technology. Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, the relationship between an antibody’s structure and function is unpredictable.
Furthermore, Kouassi et al. (TREM-1; Is It a Pivotal Target for Cardiovascular Diseases? J Cardiovasc Dev Dis. 2018 Sep 7;5(3):45) teach TREM-1 plays an important role in inflammation in cardiovascular diseases (CVDs) such as atherosclerosis and acute myocardial infarction (Pg. 9, entire ¶ 3); however, “other CVDs that are not yet studied in respect of TREM-1” (Pg. 9, last ¶, lines 2-3). This teaching indicates targeting TREM-1 is a viable method for treatment of some cardiovascular diseases. It is not readily established that all CVDs could be predictably treated with an anti-TREM-1 antibody as the association of all CVDs and TREM-1 dysfunction is not readily established.
Thus, the invention is directed towards a method with unpredictable and complex subject matter wherein practicing the claimed invention requires the anti-TREM-1 antibody sequence and the specific cardiovascular disease treated.
(2) The state of the prior art and (5) the breadth of the claims
The instant specification states treatment “encompasses an alleviation of at least one symptom of the disease, a reduction in the severity of the disease, or the delay or prevention of disease progression to more serious symptoms” (¶ 0089, emphasis added). Therefore, the phrase “treating cardiovascular disease” encompasses a variety of responses in a subject, including a preventative treatment, wherein the disease is not specified.
Cardiovascular disease is not one single disease and it “includes a variety of heart and blood vessel conditions, such as coronary artery disease, peripheral arterial disease, heart attack, stroke, high blood pressure, heart valve disease, vascular disease, aorta disease, heart failure, cardiomyopathy, abnormal heart rhythms, congenital heart disease, and many other heart and blood vessel conditions” (Cardiovascular Disease is NOT Just a Man’s Disease, Cardio-HART by Cardio-Phoenix, 2020, Pg. 2, ¶ 1), requiring different treatment plans. Therefore, the variability of cardiovascular diseases makes it difficult to predict whether a therapeutic approach effective in one disease will be effective in another.
Cardiovascular diseases could not be prevented broadly by an antigen binding protein that binds TREM-1. For example, congenital heart disease is a heart abnormality present at birth and treated commonly through surgical interventions (Bouma and Mulder, Changing Landscape of Congenital Heart Disease, Circulation Research, 2017 Mar 17, Vol 120, Issue 6, Pg. 908, entire Abstract). This teaching demonstrates that prevention of all cardiovascular diseases comprising administering the antigen binding protein that binds TREM-1 not supported as instantly claimed.
As instantly claimed, the antigen binding protein that binds TREM-1 can comprising numerous CDR combinations (claims 1-2), numerous variable amino acid residues (claims 44 and 46), up 20% variation in the light and heavy variable domains (claim 7), up to 10% variation in the light and heavy chains (claim 25), and any mutations to the framework region of the light and heavy chains (claims 17-18).
The instant specification states “’antigen binding protein’ refers to a polypeptide that is capable of specifically binding an antigen, e.g. a target or its signaling partner, or that is capable of binding an antigen with a measurable binding affinity” (¶ 0076). This definition includes multiple types of antigen binding proteins, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 4-5). In addition, antibody fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antigen binding proteins encompass a variety of species, each with their own advantages and disadvantages.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen-binding region of the antibody, i.e. anywhere in the VH and VL including the framework region, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicate amino acid substitutions within CDRs and framework regions can completely change the antigen recognition of the antibody; this problem would be further exacerbated when replacing entire CDRs. A person having ordinary skill in the art would not be able to predict which CDR sequences retain TREM-1 binding.
In addition, as instantly claimed, the antigen binding protein that binds TREM-1 can comprise any 10 mutations to the heavy chain constant regions of an IgG, IgM, IgA, IgD, or IgE, including combinations and fragments thereof (claim 19). Vafa et al. (An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations, Methods, Volume 65, Issue 1, 2014, Pages 114-126) state teach a single amino acid substitution to an Fc domain can cause repositioning of key residues responsible for interacting with FcγRs, resulting in loss of function (Pg. 124, column 1, entire ¶ 2). This teaching indicates amino acid substitutions within Fc domains can inhibit their interactions with their receptors and lead to loss of function. This issue would be compounded when combinations and fragments of heavy chain constant regions (Fcs) are taken into account. A person having ordinary skill in the art would not be able to predict which Fc domain modifications retain function.
Finally, as instantly claimed, the antigen binding protein that binds TREM-1 can comprise numerous polynucleotide sequences encoding the light and heavy variable domains of the antigen binding protein that satisfy the hybridization requirements (claim 7). Alberts et al. (Molecular Biology of the Cell, 4th edition, New York: Garland Science, 2002, Isolating, Cloning, and Sequencing DNA) teaches “[d]ifferent hybridization conditions allow less than perfect DNA matching” (Pg. 5, legend of Fig. 8-25). This teaching indicates the polynucleotide sequences can contain mutations as hybridization can produce mismatches, leading to reduced TREM-1 binding by the encoded antigen binding protein. A person having ordinary skill in the art would not be able to predict which polynucleotide sequences encode antibodies that retain their ability to bind TREM-1.
Claim 20 is drawn to the method further comprising “a therapeutically effective amount of an antigen binding protein that competes for binding to TREM-1 with an antigen binding protein of claim 1” (lines 2-3). This recitation is functional language wherein the antigen binding protein that competes for binding to TREM-1 comprises a broad genus of structurally distinct antigen binding proteins. Said proteins are defined by functional language rather than their structures. Based on the instant specification’s definition for antigen binding protein, it can comprise less than 6 CDRs. Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding. A person having ordinary skill in the art would not be able to predict the identities of the CDR(s) that produce an antibody that competes for TREM-1 binding.
Moreover, dependent claims recite:
the antigen binding protein is an IgG1 (claim 22) or monoclonal (claim 24) antibody;
the type of cardiovascular disease (claims 32 and 34);
how the treatment is administered (claims 35-36);
additional therapeutic agents (claims 37-38); and
the amino acid sequence of TREM-1 (claim 39).
Thus, the dependent claims further show the complexity of the subject matter wherein the method depends on the identity of the anti-TREM-1 antigen binding protein, the type of cardiovascular disease targeted, how the treatment is administered, and inclusion of additional therapeutic agents.
The claims recites a wider range of embodiments that goes beyond the support from the instant specification.
As fully described in the 112(a) written description section, claims 1-2, 7, 17-20, 25, 44, and 46 are drawn to genera of antigen binding proteins that bind TREM-1 or compete for TREM-1 binding. Tables 7-10 of the instant specification delineate the amino acid and nucleotide sequences of (i) the heavy and light chains (Table 7, ¶ 0239), (ii) the light and heavy chain variable domains (Table 8, ¶ 0240), (iii) the light chain CDRs 1-3 (Table 9, ¶ 0241), and (iv) the heavy chain CDRs 1-3 (Table 10, ¶ 0242) for 15 distinct anti-TREM-1 antibodies. The instant specification does support that the entire genus of variants of antigen binding proteins that bind TREM-1 as recited in claims 1-2, 7, 17-20, 25, 44, and 46 would retain their ability to bind TREM-1. The instant specification fails to teach any member of the genus of antigen binding proteins that compete for binding to TREM-1 with the antigen binding protein of claim 1 as recited in claim 20, indicating its existence is merely “contemplated” (¶ 0038). Consequently, the lack of structure delineated in the claims encompasses a vast amount of antigen binding proteins that bind TREM-1 or compete for TREM-1 binding and thus leads to a lack of enablement as Applicant failed to disclose how to use such molecules in treating cardiovascular disease.
The instant specification teaches mouse models wherein the antigen binding proteins that bind TREM-1 “reduce proinflammatory cytokine/chemokine release (acute response) and result in improved disease outcomes for atherosclerosis (Ath) and myocardial infarction (MI)” (¶ 0261). Example 6 details “reducing one or more symptoms of cardiovascular disease (e.g., atherosclerosis or myocardial infarction)” (¶ 0280), not preventing cardiovascular disease. The instant specification does not detail how said treatment could prevent cardiovascular disease nor treatment of cardiovascular disease besides atherosclerosis and myocardial infarction. Therefore, it is concluded that the instant specification provides support for reducing one or more symptoms of atherosclerosis or myocardial infarction in a subject comprising administering the antigen binding protein that binds TREM-1.
Accordingly, claims 1-2, 7, 17-20, 25, 44, and 46 are incredibly broad and drawn to a method of treating all cardiovascular disease comprising administering to a subject in need thereof a therapeutically effective amount of a genus of antigen binding proteins that binds to TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding, the full scope of which is not enabled by the methods as instantly claimed.
(3) The relative skill of those in the art, (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).
For 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 predictability of applying a genus of antigen binding proteins that bind TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding for the treatment, including prevention, of all cardiovascular diseases would be low (the predictability or unpredictability of the art) given that:
It is not predictable how the genus of variants of antigen binding proteins that bind TREM-1 as recited in claims 1-2, 7, 17-19, 25, 44, and 46 would affect its binding affinity (see Rudikoff and Colman) i.e. ability to bind TREM-1. Furthermore, the structure of the genus of antigen binding proteins that compete for TREM-1 binding of claim 20 cannot be reliably predicted from function alone (see Sevy and Meiler). There is a lack of enablement as Applicant failed to disclose how to predictably use such molecules in treating cardiovascular diseases.
Cardiovascular disease is not a single disease with one treatment plan (see Cardio-HART). Currently, there is no known prevention for all cardiovascular diseases (see Bouma and Mulder). Therefore, the antigen binding protein that binds TREM-1 would not predictably be effective in all cardiovascular diseases.
Consequently, claims 1-2, 7, 17-20, 25, 44, and 46 are directed to complex and unpredictable fields, where the successful treatment (including prevention) of all cardiovascular diseases comprising administrating to the subject a genus of antigen binding proteins that bind TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Evidence of efficacy of reducing one or more symptoms of atherosclerosis or myocardial infarction in a subject comprising administering the antigen binding protein that binds TREM-1 of Tables 7-10 is provided in the instant specification.
Therefore, a method of reducing one or more symptoms of atherosclerosis or myocardial infarction comprising administering to a subject in need thereof a therapeutically effective amount of an antigen binding protein that binds TREM-1 as recited in Tables 7-10 is supported by the specification. However, to a method of treating all cardiovascular disease comprising administering to a subject in need thereof a therapeutically effective amount of a genus of antigen binding proteins that binds to TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding is not supported.
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
Tables 7-10 of the instant specification delineate the amino acid and nucleotide sequences of (i) the heavy and light chains (Table 7, ¶ 0239), (ii) the light and heavy chain variable domains (Table 8, ¶ 0240), (iii) the light chain CDRs 1-3 (Table 9, ¶ 0241), and (iv) the heavy chain CDRs 1-3 (Table 10, ¶ 0242) for 15 distinct anti-TREM-1 antibodies. The instant specification teaches mouse models wherein the antigen binding proteins that bind TREM-1 “reduce proinflammatory cytokine/chemokine release (acute response) and result in improved disease outcomes for atherosclerosis (Ath) and myocardial infarction (MI)” (¶ 0261). Example 6 details “reducing one or more symptoms of cardiovascular disease (e.g., atherosclerosis or myocardial infarction)” (¶ 0280), not preventing cardiovascular disease.
The specification does not provide any additional examples or guidance on how said treatment could prevent cardiovascular disease nor treatment of cardiovascular disease besides atherosclerosis and myocardial infarction as instantly claimed (the amount of direction or guidance presented and the presence or absence of working examples). The specification of the instant application does not provide support for the entire scope of the claims.
The genus of antigen binding proteins that bind TREM-1 of claims 1-2, 7, 17-19, 25, 44, and 46 and the genus of antigen binding proteins that compete for TREM-1 binding of claim 20 have substantial variation. Consequently, it would require extensive screening and testing to determine which proteins are effective in treatment of cardiovascular disease.
Cardiovascular disease is not a single disease with one treatment plan (see Cardio-HART). Currently, there is no known prevention for all cardiovascular diseases (see Bouma and Mulder).
Therefore, even for a given antigen binding protein that binds TREM-1, it is not readily established which cardiovascular disease could be treated and/or prevented.
The amount of experimentation would not be reasonable because it would require determining which antigen binding proteins that bind TREM-1 with or without antigen binding proteins that compete for TREM-1 binding to use for any and all cardiovascular disease treatment (including prevention) in a subject; this is not routine and would therefore require undue experimentation (the quantity of the experimentation, see MPEP 2164.06).
Claims 1-2, 7, 17-20, 25, 44, and 46 are 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 use a genus of antigen binding proteins that binds to TREM-1 with or without a genus of antigen binding proteins that compete for TREM-1 binding to treat (including prevent) all cardiovascular diseases with a predictability of success for the reasons outlined above. Claims 4, 14, 22, 24, 32, and 34-39 are included in this rejection as they incorporate and/or depend on claim 1.
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 7, 17, 32, and 38 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.
The term “moderately stringent conditions” in claim 7 is a relative term which renders the claim indefinite. The term “moderately stringent conditions” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “moderately stringent conditions” renders the conditions needed for hybridization indefinite.
For the purposes of claim interpretation, “moderately stringent conditions” will be treated as any condition in which hybridization occurs.
Claim 17 recites the limitation "the anti- antigen-binding protein" in line 2. There is insufficient antecedent basis for this limitation in the claim.
For the purposes of claim interpretation, "the anti- antigen-binding protein" will be treated as "the antigen-binding protein".
Regarding claim 32, the phrases "stroke (ischemic and hemorrhagic)” and “peripheral vascular disease (e.g. peripheral artery disease)” render the claim indefinite because it is unclear whether the limitations in the parentheses of the phrases are part of the claimed invention or merely examples. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the phrases within the parentheses will be treated as merely examples and will not be considered part of the claimed invention.
Regarding claim 38, the phrase "a cholesterol-lowering agent, an agent that increases the expression of LDLR, statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), PCSK9 inhibitors (Repatha®, Praluent®, Leqvio®), nicotinic acid (Niacin) (NIACOR®, NIASPAN® (slow release niacin), SLO-NIACIN® (slow release niacin), Fibric acid (LOPID® (gemfibrozil), TRICOR® (fenofibrate), Bile acid sequestrants (QUESTRAN® (cholestyramine), colesevelam (WELCHOL®), COLESTID® (colestipol), Cholesterol absorption inhibitors (Zetia (ezetimibe)), combination of nicotinic acid with statin (ADVICOR® (LOVASTATIN and NIASPAN®), combination of a statin with an absorption inhibitor (VYTORIN (ZOCOR® and ZETIA®) and/or lipid modifying agents like PCSK9 inhibitors, PPAR gamma agonists, PPAR alpha/gamma agonists, squalene synthase inhibitors, cholesterylester transfer protein (CETP) inhibitors, anti-hypertensives, anti-thrombotics (aspirin) anti-diabetic agents (such as sulphonyl ureas, insulin, GLP-1 analogs, DDPIV inhibitors, SGL2 inhibitors), ApoB modulators, MTP inhibitors, Corlanor® (ivabradine) I(f) current Inhibitor, omecamtiv mecarbil cardiac myosin activator, OLPASIRAN (AMG890) (siRNA) that lowers lipoprotein(a), AMG 594 cardiac troponin activator, AMG 609, AMG 171 (Growth Differential Factor 15 (GDF 15) analog), AMG 133 (gastric inhibitory polypeptide receptor (GIPR) antagonist and glucagon-like peptide 1 (GLP-1) receptor agonist, and arteriosclerosis obliterans treatments” renders the claim indefinite because it is unclear 1) whether the limitations in the parentheses of the phrases are part of the claimed invention or merely examples and 2) the parentheses are not nested appropriately, making it difficult to distinguish which drugs are a part of which classes. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the phrase will be treated as “a cholesterol-lowering agent; an agent that increases the expression of LDLR; statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin); PCSK9 inhibitors (Repatha®, Praluent®, Leqvio®); nicotinic acid (Niacin) (NIACOR®, NIASPAN® (slow release niacin), SLO-NIACIN® (slow release niacin)); Fibric acid (LOPID® (gemfibrozil), TRICOR® (fenofibrate)); Bile acid sequestrants (QUESTRAN® (cholestyramine), colesevelam (WELCHOL®), COLESTID® (colestipol)); Cholesterol absorption inhibitors (Zetia (ezetimibe)); combination of nicotinic acid with statin (ADVICOR® (LOVASTATIN and NIASPAN®)); combination of a statin with an absorption inhibitor (VYTORIN (ZOCOR® and ZETIA®)) and/or lipid modifying agents like PCSK9 inhibitors, PPAR gamma agonists, PPAR alpha/gamma agonists, squalene synthase inhibitors; cholesterylester transfer protein (CETP) inhibitors; anti-hypertensives; anti-thrombotics (aspirin); anti-diabetic agents (such as sulphonyl ureas, insulin, GLP-1 analogs, DDPIV inhibitors, SGL2 inhibitors); ApoB modulators; MTP inhibitors; Corlanor® (ivabradine) I(f) current Inhibitor; omecamtiv mecarbil cardiac myosin activator; OLPASIRAN (AMG890) (siRNA) that lowers lipoprotein(a); AMG 594 cardiac troponin activator; AMG 609; AMG 171 (Growth Differential Factor 15 (GDF 15) analog); AMG 133 (gastric inhibitory polypeptide receptor (GIPR) antagonist and glucagon-like peptide 1 (GLP-1) receptor agonist); and arteriosclerosis obliterans treatments” to fix the nesting of the parentheses. In addition, the phrases within the parentheses will be treated as merely examples and will not be considered part of the claimed invention.
Claim 38 contains the trademark/trade names Repatha®, Praluent®, Leqvio®, NIACOR®, NIASPAN®, SLO-NIACIN®, LOPID®, TRICOR®, QUESTRAN®, WELCHOL®, COLESTID®, Zetia (missing trademark symbol)/ ZETIA®, ADVICOR® NIASPAN®, VYTORIN (missing trademark symbol), ZOCOR®, and Corlanor®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe the following:
Repatha®, Praluent®, and Leqvio® are used to identify PCSK9 inhibitors;
NIACOR®, NIASPAN®, and SLO-NIACIN® are used to identify nicotinic acids;
LOPID® and TRICOR® are used to identify fibric acids;
QUESTRAN®, WELCHOL®, and COLESTID® are used to identify bile acid sequestrants;
Zetia (missing trademark symbol)/ ZETIA® is used to identify a cholesterol absorption inhibitor;
ADVICOR® is used to identify a combination of nicotinic acid with a statin;
NIASPAN® and ZOCOR® are used to identify statins;
VYTORIN (missing trademark symbol) is used to identify a combination of a statin with an absorption inhibitor; and
Corlanor® is used to identify an I(f) current Inhibitor.
Accordingly, the identification/description is indefinite.
Regarding claim 38, the phrase "lipid modifying agents like PCSK9 inhibitors" renders the claim indefinite because it is unclear whether the limitation following the phrase “like” is part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the limitation following the phrase “like” will be treated as merely an example of a lipid modifying agent and will not be considered part of the claimed invention.
Regarding claim 38, the phrase "such as sulphonyl ureas, insulin, GLP-1 analogs, DDPIV inhibitors, SGL2 inhibitors" renders the claim indefinite because it is unclear whether the limitation following the phrase “such as” is part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the limitation following the phrase “such as” will be treated as merely examples of anti-diabetic agents and will not be considered part of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 7, 14, 25, 39, 44, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5-8 and 41-46 of copending Application No. 19/648,642 (hereinafter referred to as copending ‘642) in view of Kouassi et al. (TREM-1; Is It a Pivotal Target for Cardiovascular Diseases?, J Cardiovasc Dev Dis, 2018 Sep 7;5(3):45).
Claims 5-6 and 45 of copending ‘642 teach an antigen-binding protein that binds human TREM-1 having the amino acid sequence of SEQ ID NO: 20 (identical to instant SEQ ID NO: 2 of instant claim 39) comprising the amino acid sequences of the recited SEQ ID NOs for the 6 CDRs (identical to the instant SEQ ID NOs of instant claims 1-2 and 4 as shown in the table below).
Instant SEQ ID NOs for CDRs
SEQ ID NOs of 19/648,642 for CDRs
10-12 and 16-18
30-32 and 36-38
30-32 and 36-38
50-52 and 56-58
50-52 and 56-58
70-72 and 76-78
70-72 and 76-78
90-92 and 96-98
90-92 and 96-98
110-112 and 116-118
110-112 and 116-118
130-132 and 136-138
130-132 and 136-138
150-152 and 156-158
150-152 and 156-158
170-172 and 176-178
170-172 and 176-178
190-192 and 196-198
190-192 and 196-198
210-212 and 216-218
210-212 and 216-218
230-232 and 236-238
230-232 and 236-238
250-252 and 256-258
250-252 and 256-258
270-272 and 276-278
270-272 and 276-278
290-292 and 296-298
544-546 and 550-552
2190-2192 and 2196-2198
Claims 7-8 and 46 of copending ‘642 teach the light and heavy variable domains of the antigen binding protein comprise amino acid sequences having at least 80% (claim 7 of copending ‘642) or 90% (claim 8 of copending ‘642) sequence identity to the recited SEQ ID NOs (identical to the instant SEQ ID NOs of instant claims 7, 14, and 25 as shown in the table below).
Instant SEQ ID NOs for VH/VL
SEQ ID NOs of 19/648,642 for VH/VL
21/22
41/42
41/42
61/62
61/62
81/82
81/82
101/102
101/102
121/122
121/122
141/142
141/142
161/162
161/162
181/182
181/182
201/202
201/202
221/222
221/222
241/242
241/242
261/262
261/262
281/282
281/282
301/302
539/540
2185/2186
Claim 41 of copending ‘642 teaches the antigen binding protein comprises SEQ ID NOs: 2199, 2200, 2201, 2202, 2205, and 2203, which are identical to instant SEQ ID NOs: 553, 554, 555, 556, 559, and 557 of instant claim 44 respectively. Claim 42 of copending ‘642 teaches the antigen binding protein comprises SEQ ID NOs: 2212, 2219, 2222, 2227, 2230, and 2670, which are encompassed by instant SEQ ID NOs: 553, 554, 555, 556, 559, and 557 of instant claim 44 respectively.
Claim 43 of copending ‘642 teaches the antigen binding protein comprises SEQ ID NOs: 2204-2210, which are identical to instant SEQ ID NOs: 558, 560, 561, 563, 564, and 565 of instant claim 46 respectively. Claim 44 of copending ‘642 teaches the antigen binding protein comprises SEQ ID NOs: 2213, 2220, 2223, 2228, 2231, and 2671, which are encompassed by instant SEQ ID NOs: 558, 560, 561, 563, 564, and 565 of instant claim 46 respectively.
The claims of copending ‘642 do not teach a method of treating cardiovascular disease in a subject (instant claim 1). This deficiency is remedied by Kouassi et al.
Kouassi et al. teach “TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions, such as acute myocardial infarction (AMI)” (Pg. 1, Abstract, lines 12-13) wherein “any modulation of TREM-1 during the management of AMI will be beneficial for the patient” (Pg. 9, ¶ 4, lines 2-3) to reduce proinflammatory reactions. This teaching gives motivation for using the antigen binding protein in a method of treating cardiovascular disease (i.e. acute myocardial infarction) in a subject (i.e. a patient) to reduce inflammatory processes associated with TREM-1 that contribute to disease pathogenesis.
The involvement of TREM-1 in cardiovascular disease was known prior to the effective filing date of the application. In addition, copending ‘642 and Kouassi et al. are in analogous arts (i.e. TREM-1). Since Kouassi et al. teach modulation of TREM-1 can reduce inflammatory processes that contribute to cardiovascular disease pathogenesis, specifically acute myocardial infarction, in a patient, there is motivation for using the antigen binding protein as taught by copending ‘642 in a method of treating cardiovascular disease in a subject as taught by Kouassi et al.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Kouassi et al. teach modulation of TREM-1 can reduce inflammatory processes that contribute to cardiovascular disease pathogenesis, specifically acute myocardial infarction, in a patient) would have led one of ordinary skill to modify copending ‘642 (i.e. using the antigen binding protein as taught by copending ‘642 in a method of treating cardiovascular disease in a subject as taught by Kouassi et al.) to arrive at the claimed invention. There is a reasonable expectation of success as the involvement of TREM-1 in cardiovascular disease was known prior to the effective filing date of the application. Kouassi et al. indicate modulation of TREM-1 can be beneficial for therapeutic outcomes in a patient, applicable to the anti-TREM-1 antigen binding protein of copending ‘642. In addition, copending ‘642 and Kouassi et al. are in analogous arts (i.e. TREM-1).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the antigen binding protein as taught by copending ‘642 in a method of treating cardiovascular disease in a subject as taught by Kouassi et al.
This is a provisional nonstatutory double patenting rejection.
Art-Free Subject Matter
It is noted that SEQ ID NOs of claims 4 and 14 have been thoroughly searched corresponding to the limitations of the claims and are free of prior art.
Conclusion
Claims 1-2, 4, 7, 14, 17-20, 22, 24-25, 32, 34-39, 44, and 46 are currently under consideration for patentability under 37 CFR 1.104. Claims 1-2, 4, 14, 17-18, 22, 24, 38, 44, and 46 are objected to. Claims 1-2, 4, 7, 14, 17-20, 22, 24-25, 32, 34-39, 44, and 46 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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