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 .
Election/Restrictions
Applicant's election with traverse of Group I and the species, A77E, K125R, V165Q, H170T, A280V in the reply filed on 12/23/2025 is acknowledged. The traversal is on the ground(s) that Grover does not disclose a modified protein M (or fragment thereof) with one or more amino acid mutations as instantly claimed. This is not found persuasive because the fragment Grover discloses is specifically recited in instant claim 5. Further, a deletion is a modification of a protein sequence. Finally, Grover specifically recites variants of said fragment.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-15, 19, 40, 47, 50, and 54 are pending. Claims 9-15, 40, 47, 50, and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Claims 1-8 and 19 are currently under examination.
Information Disclosure Statement
The information disclosure statements filed on 8/3/2023, 9/6/2023, and 1/9/2026 have been considered. Signed copies are enclosed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8 and 19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a modified mycoplasma protein M or a functional fragment thereof, having one or more amino acid mutations that increase or maintain pH stability or thermostability of the mycoplasma protein M or a functional fragment thereof relative to wild-type mycoplasma protein M or a functional fragment thereof, wherein thermostability is maintained up to 75 degrees, 70 degrees, 65 degrees, 60 degrees, 55 degrees, 50 degrees, 45 degrees, 40 degrees, or 38 degrees and/or wherein pH stability is maintained from a pH of 2 to 8, from a pH of 2.5 to 7.5, or from a pH of 4.5 to 7.5.
The claims have no limit to the number or type of mutations (except for claim 8, where the mutations are not possible) and encompass fragments as short as 4 amino acids. Even where specific residues are recited, the mutations are not limited to only those residues. Therefore, there are an absolutely astronomical number of possible polypeptides encompassed by the claims. These polypeptides are required to have maintained or increased thermostability and/or pH stability. Fragments are required (by the definition in the specification) to substantially retain at least one (or all) of the biological activities normally associated with the unmodified polypeptide. The specification provides antibody binding as an example of these activities, but any activity that can be associated with protein M is encompassed.
The specification discloses many point mutations and their effect on stability of the protein M variant. However, these mutations were, generally, single point mutations, and were only done within residues 78-468. These tested mutants do not take into account alterations other than these point mutations or sections outside that particular fragment. Further, they do not account for fragments of the protein. For example, the binding of protein M to antibodies is considered in the art to work by the “hug of death” where antibodies are bound in such a way to block the binding site. This is unlikely to happen with a fragment that is only 4 amino acids long. Therefore, the claims encompass far more possible polypeptides that are tested in the specification.
These peptides have no correlation between their structure and function. The claim requires specific activity, but the specification provides no guidance regarding which variants or fragments are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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.) 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.)
With the exception of mutants disclosed in the specification, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, 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 for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
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.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner (i.e. maintain the activity of protein M and maintain the thermos- and pH stability).
Therefore, the full breadth of the claims does not meet the written description provision of 35 USC 112, first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
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 1-8 and 19 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 pre-AIA the applicant regards as the invention.
Claims 1-8 and 19 are rendered indefinite by the phrase “functional fragment”. The specification (in paragraph 0080) defines "functional fragment" as one that substantially retains at least one biological activity normally associated with that polypeptide (e.g., antibody binding). The specification then goes on to state that a "functional fragment" substantially retains all of the activities possessed by the unmodified polypeptide. Therefore, a functional fragment is required to have all of the activities of the unmodified polypeptide but also to only have at least one of the activities. Therefore, it is not clear what is required for a functional fragment to meet the limitations of the claims.
Claim 1 is rendered indefinite by the term “degrees”. There are multiple temperature scales and it is not clear which one applicant is referring to.
Claim 3 recites the limitation "derivative thereof" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 is rendered indefinite by the phrase “A77E, K125R, V165Q, H170T, and A280V of M. pneumoniae protein M (SEQ ID NO:23).” Based on the sequence listing, none of these mutations are possible as the residues do not match.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-6 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grover et al (US Patent Application Publication 2015/0246953, 2015; IDS filed 8/3/2023).
The instant claims are drawn to a modified mycoplasma protein M or a functional fragment thereof, having one or more amino acid mutations that increase or maintain pH stability or thermostability of the mycoplasma protein M or a functional fragment thereof relative to wild-type mycoplasma protein M or a functional fragment thereof, wherein thermostability is maintained up to 75 degrees, 70 degrees, 65 degrees, 60 degrees, 55 degrees, 50 degrees, 45 degrees, 40 degrees, or 38 degrees and/or wherein pH stability is maintained from a pH of 2 to 8, from a pH of 2.5 to 7.5, or from a pH of 4.5 to 7.5.
Grover et al disclose a protein M fragment from M genitalium that is residues 74-468 (see paragraph 0022) of the instantly claimed SEQ ID NO:1. They also disclose a fragment that is residues 37-556 linked to a HIS tag and a thrombin cleavage site (see paragraph 0019). Deletion of amino acids from a sequence constitutes a modification of said sequence. Therefore, the fragments disclosed are modified fragments. As these fragments are specifically recited by the instant claims, they would necessarily have the same functional characteristics as those recited in the claims.
Claims 1-7 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grover et al (US Patent Application Publication 2017/0320921, 2017; IDS filed 8/3/2023).
The instant claims are drawn to a modified mycoplasma protein M or a functional fragment thereof, having one or more amino acid mutations that increase or maintain pH stability or thermostability of the mycoplasma protein M or a functional fragment thereof relative to wild-type mycoplasma protein M or a functional fragment thereof, wherein thermostability is maintained up to 75 degrees, 70 degrees, 65 degrees, 60 degrees, 55 degrees, 50 degrees, 45 degrees, 40 degrees, or 38 degrees and/or wherein pH stability is maintained from a pH of 2 to 8, from a pH of 2.5 to 7.5, or from a pH of 4.5 to 7.5.
Grover et al disclose a protein M fragment from M genitalium that is residues 74-468 (see paragraph 0005) of the instantly claimed SEQ ID NO:1. They also disclose a fragment that is residues 37-556 linked to a HIS tag and a thrombin cleavage site (see paragraph 0011). Deletion of amino acids from a sequence constitutes a modification of said sequence. Therefore, the fragments disclosed are modified fragments. As these fragments are specifically recited by the instant claims, they would necessarily have the same functional characteristics as those recited in the claims. Additionally, Grover et al disclose SEQ ID NO:18, which is a modified protein M that contains a mutation at residue 280 compared to the instantly claimed SEQ ID NO:23. As the disclosed SEQ ID NO:18 meets all of the structural requirements of the claims, if the invention works as applicant claims, this polypeptide would necessarily have the same functional characteristics as those recited in the claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian J Gangle whose telephone number is (571)272-1181. The examiner can normally be reached M-F, 9-6:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN GANGLE/ Primary Examiner, Art Unit 1645
