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 .
Status of Application, Amendments and/or Claims
The amendment of 06 January 2026 has been entered in full. Claims 6 and 11 are amended.
Claims 1-15 are pending.
Election/Restrictions
Applicant’s election of Group I, claims 1-5, drawn to a pharmaceutical composition, in the reply filed on 06 January 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)).
Claims 6-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06 January 2026.
Claims 1-5 are under consideration in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 28 April 2025 and 18 April 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
It is noted on the IDS of 28 April 2025, citation #C4 has been crossed off by the Examiner because it is not in English and there is no concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information.
Drawings
1. The replacement drawings were received on 26 June 2023. These drawings are not acceptable. Specifically, the drawing sheets are not labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d).
Claim Objections
2. Claim 1 is objected to because of the following informalities:
2a. In claim 1, line 2, for clarity, after recitation of “for treating, preventing or ameliorating heart failure”, the phrase, “wherein said pharmaceutical comprises” should be inserted.
Appropriate correction is required.
Specification
3. The disclosure is objected to because of the following informalities:
3a. At page 10, line 19, the specification discloses that SEQ ID NO: 4 is a gene sequence. However, according to the sequence listing and other locations in the specification (such as page 3, lines 18-20), SEQ ID NO: 4 is an amino acid sequence. Therefore, it is not clear what “gene sequence” the specification is intending to refer to.
Furthermore, at page 5, lines 9-11, the specification states, “The nucleotide encoding the soluble TREM2 protein or fragment thereof according to the present invention may have an amino acid sequence represented by SEQ ID NO: 4 or 5”. This sentence is not clear because nucleotides do not have amino acid sequences. Applicant is reminded that proteins comprise amino acid sequences.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
4. Claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., law of nature or natural phenomenon) without significantly more.
Claim 1 recites a pharmaceutical composition for treating, preventing or ameliorating heart failure, comprising TREM2 (triggering receptor expressed on myeloid cells 2) protein or a fragment thereof.
Claim 2 recites that the amino acid sequence of the TREM2 protein comprises the amino acid sequence of SEQ ID NO: 2.
Claim 3 recites that the TREM2 protein is soluble.
Claim 4 recites that the amino acid sequence of the TREM2 protein comprises the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5.
The instant claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim 1 recites to a pharmaceutical composition for treating, preventing or ameliorating heart failure, comprising TREM2 protein or a fragment thereof, and thus the claims are directed to a composition of matter, which is one of the statutory categories of invention (see MPEP §2106, subsection III, step 1 of the subject matter eligibility test in the 2019 Revised Patent Subject Matter Eligibility Guidance). Additionally, the claim limitations set forth a judicial exception (see MPEP §2106, subsection III, 2019 Revised Eligibility Guidance, revised step 2A, Prong One: Yes) because the claims recite a TREM2 protein, which is a natural phenomenon (i.e., product of nature). For example, Sleeman et al. teach a polypeptide expressed in lymph node stromal cells of fsn -/- mice that comprises the amino acid sequence of SEQ ID NO: 50 (column 3, lines 14-25), which is 100% identical to the instant TREM2 amino acid sequence of SED ID NO: 4. Colonna et al. (U.S. Patent 11,066,456) also disclose that TREM proteins are selectively expressed on different types of myeloid cells, such as mast cells, monocytes, macrophages, dendritic cells, and neutrophils, and may have a predominant role in immune and inflammatory processes (column 7, lines 1-4).
Based upon the limited disclosure in the specification, there is no indication that the TREM2 protein of the claims has any characteristics (structural, functional, or otherwise) that is different from naturally occurring TREM2 protein. Thus, the claims are directed to product claims that recite TREM2 that is a natural product that is not markedly different in structure or function from a naturally occurring TREM2 protein. The claims also do not recite any additional elements that integrate the judicial exception into a practical application (revised step 2A: Prong Two: No). Although claims 1-5 recite a “pharmaceutical composition” comprising the TREM2 protein, there are no other ingredients of the composition recited. Furthermore, the TREM2 could simply be in water. The limitations of claims 1-5 do not provide any structural features to the pharmaceutical composition that make it markedly different from how TREM2 occurs in nature. The formulation is insignificant extra-solution activity and amounts to nothing more than a mere field of use.
Furthermore, even if the claims recited a specific buffer/carrier/excipient, there is no indication in the specification that mixing such components with TREM2 changes the structure, function, or other properties of TREM2. In other words, the overall combination of TREM2 and a buffer/carrier/excipient in the pharmaceutical composition does not render the resulting composition different from each of the components alone. There is no difference in function and no difference in structure (i.e., there are no structural changes to TREM2 protein). As there are no different characteristics between the claimed nature-based product and its natural counterpart, the claimed composition does not have any markedly different characteristics and the claims as a whole do not amount to significantly more than the "product of nature" by itself (step 2B: No). The claimed pharmaceutical composition is similar to the novel bacterial mixture of Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948), which was held ineligible because each species of bacteria in the mixture (like the TREM2 in the instant composition) continued to have “the same effect it always had”, i.e., it lacked markedly different characteristics. See Funk Brothers discussed in Association for Molecular Pathology v. Myriad Genetics, 569 U.S. __, 133 S. Ct. at 2117, 106 USPQ2d 1972 (2013).
The instant claims do not recite elements in addition to the judicial exception that impose meaningful limits on the claim scope. Therefore, the instant claims as a whole do not amount to significantly more than the exception itself (step 2B: No) and do not qualify as eligible subject matter under 35 U.S.C. §101. See also Diamond v. Chakrabarty, 447 U.S. 303 (1980) and Association for Molecular Pathology v. Myriad Genetics, 569 U.S. __, 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013) and chttp://www.uspto.gov/patents/law/exam/examguide.jsp.
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.
5. Claims 2 and 4 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.
5a. Claims 2 and 4 recite the limitation "the amino acid sequence" in line 1. There is insufficient antecedent basis for this limitation in the claims. Claim 1, from which claims 2 and 4 depend, does not recite “an/the amino acid sequence” of TREM2 protein. It is noted that this issue could be overcome by amending claim 2 to recite, for example, “The pharmaceutical composition of claim 1, wherein
Likewise, claim 4 can be amended to recite, for example, “The pharmaceutical composition of claim 3, wherein
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1, from which claim 5 depends, recites a pharmaceutical composition for treating, preventing or ameliorating heart failure, comprising TREM2 (triggering receptor expressed on myeloid cells 2) protein or a fragment thereof.
Claim 5 recites the pharmaceutical composition of claim 1, wherein the heart failure is a complication that occurs after the onset of myocardial infarction.
However, claim 5 does not further limit the claimed subject matter of claim 1. For example, claim 5 only recites limitations directed to the intended use limitation in claim 1 and does not recite any limitations that further limit the claimed pharmaceutical composition. It is also noted that the invention of claim 1 is a product and not a method. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
7. Claims 1, 3, and 5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a pharmaceutical composition for treating, preventing or ameliorating heart failure, comprising TREM2 (triggering receptor expressed on myeloid cells 2) protein or a fragment thereof. Claim 3 recites that the TREM2 protein is soluble.
The specification of the instant application teaches that TREM2 is a receptor that carries out signal transmission through an adapter protein called DAP12 and it is known to regulate myeloid function (page 2, lines 13-15). TREM2 is also involved in immunomodulation and plays a role in phagocytosis of dementia target factor and amyloid-beta (page 2, lines 16-19). The specification teaches that the pharmaceutical composition includes a variant which is capable of functionally acting equivalently TREM2 protein or a fragment thereof (page 5, lines 11-14). The specification discloses that variants are generated by deletions, substitutions, or insertions and may include sequences at least 70%, 80%, 90%, 95% homology to SEQ ID NOs: 4 and 5, for example (page 5, lines 15-17).
Therefore, in view of the teachings of the instant specification, the “TREM2 protein or a fragment thereof” limitations are broadly interpreted by the Examiner has reading upon any TREM2 protein or fragment, with any number of deletions, substitutions, or insertions. However, the specification does not teach any variants or fragments of TREM2, other than the amino acid sequences of SEQ ID NOs: 2, 4, and 5.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the factors present in the claims for the claimed pharmaceutical composition are (1) structural characteristics of a TREM2 protein or fragment thereof and (2) a functional characteristic of treating, preventing, or ameliorating heart failure. There is no identification of any particular sequence or structure of the TREM2 protein or fragment thereof that must be conserved in order to provide the required function of treating, preventing, or ameliorating heart failure. Thus, the claims are drawn to a genus of TREM2 proteins/fragments.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of TREM2 proteins/fragments and the function of treating, preventing, or ameliorating heart failure. In other words, the specification does not teach the structure which results in an amino acid sequence with the claimed required characteristics. The description of the TREM2 protein amino acid sequences of SEQ ID NOs: 2, 4, and 5 is not adequate written description of an entire genus of TREM2 proteins and fragments thereof.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, clearly states that “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). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). 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). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of a TREM2 protein and fragment with any possible amino acid sequence (encompassing all possible deletions, substitutions, or insertions), 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 protein 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 a TREM2 protein comprising the amino acid sequence of SEQ ID NO: 2, 4, or 5, but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
8. Claims 1-5 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 pharmaceutical composition for treating or ameliorating heart failure, wherein said composition comprises a TREM2 protein comprising the amino acid sequence of SEQ ID NO: 2, 4, or 5, does not reasonably provide enablement for a pharmaceutical composition for treating, preventing or ameliorating heart failure, wherein said composition comprises a TREM2 protein or fragment thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1 recites a pharmaceutical composition for treating, preventing or ameliorating heart failure, comprising TREM2 (triggering receptor expressed on myeloid cells 2) protein or a fragment thereof. Claim 3 recites that the TREM2 protein is soluble.
(I) The specification of the instant application teaches that TREM2 is a receptor that carries out signal transmission through an adapter protein called DAP12 and it is known to regulate myeloid function (page 2, lines 13-15). TREM2 is also involved in immunomodulation and plays a role in phagocytosis of dementia target factor and amyloid-beta (page 2, lines 16-19). The specification teaches that the pharmaceutical composition includes a variant which is capable of functionally acting equivalently TREM2 protein or a fragment thereof (page 5, lines 11-14). The specification discloses that variants are generated by deletions, substitutions, or insertions and may include sequences at least 70%, 80%, 90%, 95% homology to SEQ ID NOs: 4 and 5, for example (page 5, lines 15-17).
Therefore, in view of the teachings of the instant specification, the “TREM2 protein or a fragment thereof” limitations are broadly interpreted by the Examiner has reading upon any TREM2 protein or fragment, with any number of deletions, substitutions, or insertions. However, the specification does not teach any variants or fragments of TREM2, other than the amino acid sequences of SEQ ID NOs: 2, 4, and 5.
There are no methods or working examples in the specification that indicate all possible TREM2 proteins and fragments thereof treat, prevent, or ameliorate heart failure. A large quantity of experimentation would be required of the skilled artisan to generate all possible TREM2 proteins and fragments with any amino acid possible sequence (encompassing all possible deletions, substitutions, or insertions), and then screen such for treating, preventing, or ameliorating heart failure. Such experimentation is considered undue. Additionally, one skilled in the art would not be able to predict that all possible TREM2 proteins and fragments would have the desired functional activity of treating, preventing, or ameliorating heart failure. A person of skill in the art would not know which amino acid residues are considered essential and which are non-essential. Without detailed direction as to which amino acids are essential to the function of the TREM2 protein, the skilled artisan would not be able to determine without undue experimentation which sequences encompassed by the instant claims would exhibit the desired functional characteristics of treating, preventing, or ameliorating heart failure.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the DNA and protein which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427).
See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph).
Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
Due to the large quantity of experimentation necessary to generate all possible TREM2 proteins and fragments thereof and screen such for the desired functional activities of treating, preventing, or ameliorating heart failure; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
(II) Example 2 of the instant specification teaches administration of soluble TREM2 (SEQ ID NO: 4 or SEQ ID NO: 5) to ischemic mouse hearts in a myocardial infarction mouse model (pages 10-11). The specification indicates that infarcted size of the heart tissue is reduced in mice administered sTREM2 (page 11, lines 8-14; Figure 4). Additionally, the left ventricular ejection fraction and left ventricular shortening rate increased and the end-systolic volume decreased in the sTREM2 group (page 11, lines 15-20).
Regarding instant claim 1, it is noted that the Examiner has interpreted the phrase “for treating, preventing or ameliorating heart failure” as an intended use of the claimed pharmaceutical composition. Furthermore, for the specific recitation of “preventing”, the instant specification teaches “’prevention’ is the prophylactic treatment of a disease state to reduce and/or minimize the risk and/or risk of recurrence of the disease state by administering to the patient a therapeutically effective amount of the soluble TREM2 protein” (page 7, lines 18-20). The specification continues to disclose that prophylactic treatment can be divided into primary prevention and secondary prevention, wherein primary prevention is treatment aimed at reducing or minimizing the risk of a disease state in a patient for whom the clinical disease state has not yet manifested (page 7, lines 24-26). Meanwhile, secondary prevention is minimizing or reducing the risk of recurrence or secondary recurrence of the same or similar clinical disease state (page 7, lines 27-28). that if a certain disease has not developed, it falls under “prevention of onset” (page 19, [0027]).
Thus, one interpretation of the term “preventing” by the Examiner is that an activity will not occur, i.e. heart failure will not occur. However, there are no methods or working examples in the specification that indicate prevention of heart failure by administration a TREM2 protein or fragment thereof. The instant specification is only enabling for treatment or amelioration of heart failure by administering a TREM2 protein comprising the amino acid sequence of SEQ ID NO: 2, 4, or 5. A large quantity of experimentation would be required of the skilled artisan to determine the quantity of the TREM2 protein to be administered and the duration of administration to prevent heart failure. Such trial and error experimentation is considered undue. The limited teachings of the specification are not adequate guidance, but are merely an invitation for the artisan to use the current invention as a starting point for further experimentation. The claimed method may not necessarily prevent heart failure. Applicant is reminded that a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Due to the large quantity of experimentation necessary to prevent heart failure by administering a TREM2 protein or fragment thereof; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
9. Claims 1 and 3-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sleeman et al. (U.S. Patent 6,797,271; issued 28 September 2004).
Sleeman et al. teach a polypeptide expressed in lymph node stromal cells of fsn -/- mice that comprises the amino acid sequence of SEQ ID NO: 50 (column 3, lines 14-25). It is noted that the amino acid sequence of SEQ ID NO: 50 of Sleeman et al. is 100% identical to the instant TREM2 amino acid sequence of SED ID NO: 4, meeting the limitations of instant claims 1 and 4 (see sequence alignment, below).
Sequence 50, US/09823038A
Patent No. 6797271
GENERAL INFORMATION
APPLICANT: Strachan, Lorna
APPLICANT: Sleeman, Matthew
APPLICANT: Abernethy, Nevin
APPLICANT: Onrust, Rene
APPLICANT: Kumble, Anand
APPLICANT: Murison, Greg
TITLE OF INVENTION: Compositions Isolated From Stromal Cells
TITLE OF INVENTION: and Methods For Their Use
FILE REFERENCE: 11000.1037c3
CURRENT APPLICATION NUMBER: US/09/823,038A
CURRENT FILING DATE: 2001-07-09
NUMBER OF SEQ ID NOS: 61
SEQ ID NO 50
LENGTH: 227
TYPE: PRT
ORGANISM: Mouse
Query Match 100.0%; Score 820; Length 227;
Best Local Similarity 100.0%;
Matches 158; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPC 60
Qy 61 QRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEV 120
Qy 121 LQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHS 158
||||||||||||||||||||||||||||||||||||||
Db 121 LQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHS 158
Sleeman et al. disclose that the polypeptide may be administered to treat cardiac failure (column 3, lines 49-63). Sleeman et al. also state that the polypeptide is present within a pharmaceutical composition, meeting the limitations of instant claim 1 (column 12, lines 1-13, 39-65).
Claim Rejections - 35 USC § 102 and § 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Colonna et al. (U.S. Patent 11,066,456; 20 July 2021), as evidenced by Genbank Accession No. NM_00127078 (ROD 23 July 2024), Schmid et al. (“Schmid1” J Neurochem 83: 1309-1320, 2002), and Schmid et al. (“Schmid2”, Genbank Accession No. AAO06114.1, 25 December 2002).
Colonna et al. teach TREM2 polypeptides and pharmaceutical compositions comprising such, meeting the limitations of instant claim 1 (column 1, lines 66-67 through column 2, lines 1-35; column 6, lines 53-63; column 19, lines 56-67 through column 20, lines 1-61). Colonna et al. disclose that the TREM2 of the invention can be found in a variety of species, such as mouse, and cite Genbank Accession No. NM_001272078.1 (column 8, lines 13-16).
It is noted that the entry for Genbank Accession No. NM_001272078.1 provides a mouse TREM2 nucleic acid sequence and amino acid sequence. The TREM2 amino acid sequence encoded by the nucleic acid sequence of Genbank Accession No. NM_001272078.1 is 100% identical to the amino acid sequence of SEQ ID NO: 2 of the instant application (see sequence alignment, below). Furthermore, Schmid1, which is annotated in the Genbank Accession No. NM_001272078.1 entry, and Schmid2 also disclose the TREM2 protein of SEQ ID NO: 2 of the instant claims (see Schmid1, page 1311, bottom of column 2 through page 1312, column 2; Figure 6;; entirety of Schmid2).
Qy=instant SEQ ID NO: 2
Db= amino acid sequence encoded by Genbank Accession No. NM_00127078
RESULT 1
AASEQ2_02072026_155159
Query Match 100.0%; Score 1337; DB 1; Length 249;
Best Local Similarity 100.0%;
Matches 249; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPC 60
Qy 61 QRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEV 120
Qy 121 LQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHSTSRQVSSCGSPLAYHLPPLSKE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHSTSRQVSSCGSPLAYHLPPLSKE 180
Qy 181 SRDLLPTHLHSSPPGLRSPEQVSCSQHPLGCGQGQAEAGNTCGQRAGLWPRCWAPTSDPH 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SRDLLPTHLHSSPPGLRSPEQVSCSQHPLGCGQGQAEAGNTCGQRAGLWPRCWAPTSDPH 240
Qy 241 WTRRYVREF 249
|||||||||
Db 241 WTRRYVREF 249
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Chen et al. Am J Respir Crit Care Med 188(2): 201-212, 2013 (teach TREM2 plays a rold in host defense to sepsis by enhancing bacterial clearance)
Jung et al. Nature Comm 13: 4580, August 2022 (teach that injection of soluble TREM2 leads to functional and structural improvements in infarcted hearts)
Kim et al. Int J Mol Sci 24: 5556, March 2023 (teach in vivo injection of TREM2 during subacute phase of myocardial infarction improves myocardial function and remodeling of infarcted mice hearts)
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BEB
Art Unit 1647
06 February 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647