DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I, claims 1-9 and the Species SEQ ID NO: 6, in the reply filed on 12/16/25 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Claims 10-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
NOTE: SEQ ID NO: 7 was examined along with the elected Species, SEQ ID NO:6, given the proteins’ very high degree of homology to one another.
Claim Rejections - 35 USC § 112-2nd paragraph
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 1-6 and 9 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. Appropriate clarification and/or correction is required.
Claims 1-6 are vague and indefinite because it the mere recitation of a name, i.e., a recombinant chimeric protein comprising at least one genetically engineered mutant Treponema denticola Factor H Binding Protein (FhbB) with at least one mutation compared to wild type FhbB primary sequence, to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. The claim should provide any structural properties, such as the amino acid sequence of the chimeric protein, which would allow for one to identify the claimed chimeric protein without ambiguity. Dependent claims 5 and 6 recite a plurality of genetically engineered mutant T. denticola FhbBs and also do not recite a structure. Appropriate clarification and/or correction is required.
Claims 2 and 3 vague and indefinite for the reasons above, as well as for the recitation of amino acid positions, yet no reference sequence is provided in the claim. The claims must stand alone. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow for one to identify what is being claimed. Appropriate clarification and/or correction is required.
Claim Objections
Claim 7 is objected to because of the following informalities: it comprises only non-elected Species SEQ ID NOS: 1-5, e.g., it does not contain the elected Species. SEQ ID NOS: 1-5 have only 20-25% homology to elected SEQ ID NO: 6 and re-joined SEQ ID NO: 7 (claim 8). Accordingly, if SEQ ID Nos: 1-5 (claim 7) were joined with SEQ ID Nos: 6 and 7 (claim 8) an improper Markush grouping of alternatives rejection would be made.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The alternatives SEQ ID NOS: 1-5 defined by the Markush grouping do not share both a single structural similarity and a common use with the proteins of SEQ ID Nos: 6 and 7.
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claim Rejections - 35 USC § 112-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 9 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 claims are drawn to, for example:
1. (original) A recombinant chimeric protein comprising at least one genetically engineered mutant Treponema denticola Factor H Binding Protein B (FhbB) which comprises at least one mutation compared to a wild type FhbB primary sequence, wherein the at least one mutation prevents binding of the genetically engineered mutant T. denticola FhbB to Factor H (FH).
2. (currently amended) The recombinant chimeric protein of claim 1, wherein the at least one mutation includes a substitution at amino acid position 42, 43, 45, 57, 58, 64,64, 68, 93 and/or 96 of wild type FhbB primary sequence.
3. (original) The recombinant chimeric protein of claim 1, wherein the at least one mutation is at one or both of amino acid positions 45 and 58.
4. (original) The recombinant chimeric protein of claim 1, wherein the at least one mutation is an alanine substitution.
5. (original) The recombinant chimeric protein of claim 1, wherein the recombinant chimeric protein comprises a plurality of genetically engineered mutant T. denticola FhbBs. 6. (original) The recombinant chimeric protein of claim 1, wherein the recombinant chimeric protein comprises 2, 3, 4, 5 or 6 genetically engineered mutant T. denticola FhbBs.
9. (currently amended) A vaccine composition comprising a recombinant protein of claim 1.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the Genus of mutant T. denticola chimeric FhbB proteins with at least one mutation compared to wild-type which prevents binding of the genetically engineered mutant T. denticola FhbB to Factor H (FH), such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed.
The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" inquiry, whatever is now claimed. See Vas-Cath, Inc. v. Mahurkar,935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).Furthermore, the written description provision of 35 USC § 112 is severable fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The nucleic acid [product] itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, paragraph 1, "'Written Description" Requirement (66 FR 1099-1111, January 5,2001) state, "[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention" (Id. at 1104). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. The Guidelines further state, "[f]or inventions 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'" (Id. at 1106);accordingly, it follows that an adequate written description of a genus cannot beachieved in the absence of a disclosure of at least one species within the genus. Asevidenced by Greenspan et al (Nature Biotechnology 7: 936-937, 1999), definingepitopes is not as easy as it seems. Greenspan et al recommends defining anepitope by the structural characterization of the molecular interface between theantigen and the antibody is necessary to define an "epitope" (page 937, column 2).According to Greenspan et al, an epitope will include residues that make contactswith a ligand, here the antibody, but are energetically neutral, or even destabilizingto binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affectbinding. There is a limit to how much substitution can be tolerated before the originaltertiary structure is lost. Therefore, absent a detailed and particular description of arepresentative number, or at least a substantial number of the members of thegenus of mutants, the skilled artisan could not immediately recognize that Applicants were in possession of the claimed genus of at the time of filing.
Therefore, because the art is unpredictable, in accordance with the WrittenDescription Guidelines, the recitation of “at least one mutation compared to wild-type” or substitutions with no reference sequence (claims 2-4). The scope of the claim includes numerous structural variants/mutants, and the genus is highly variant because a significant number of structural differences between genus members is permitted. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
The level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which mutations (any substitution, deletion, insertion in claims 1, 5 and 6; and the substitutions without the substituted amino acid and the reference sequence recited in claims 2 and 3, in any T.denticola H Binding protein B (FhbB) which prevent binding of the genetically engineered mutant T. denticola FhbB to Factor H (FH). 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 mutant chimeric FhbB proteins.
Claim Rejections - 35 USC § 112-Scope of Enablement
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 1-3, 6-9, 14, 16, 19, 26, 28, 29, 31, 38 and 39 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 recombinant chimeric genetically engineered mutant Treponema denticola Factor H Binding Protein B (FhbB) protein comprising the amino acid sequence set forth in SEQ ID NOs: 6 or 7, wherein the protein does not bind to Factor H (FH).
, does not reasonably provide enablement for:
1. (original) A recombinant chimeric protein comprising at least one genetically engineered mutant Treponema denticola Factor H Binding Protein B (FhbB) which comprises at least one mutation compared to a wild type FhbB primary sequence, wherein the at least one mutation prevents binding of the genetically engineered mutant T. denticola FhbB to Factor H (FH).
2. (currently amended) The recombinant chimeric protein of claim 1, wherein the at least one mutation includes a substitution at amino acid position 42, 43, 45, 57, 58, 64,64, 68, 93 and/or 96 of wild type FhbB primary sequence.
3. (original) The recombinant chimeric protein of claim 1, wherein the at least one mutation is at one or both of amino acid positions 45 and 58.
4. (original) The recombinant chimeric protein of claim 1, wherein the at least one mutation is an alanine substitution.
5. (original) The recombinant chimeric protein of claim 1, wherein the recombinant chimeric protein comprises a plurality of genetically engineered mutant T. denticola FhbBs. 6. (original) The recombinant chimeric protein of claim 1, wherein the recombinant chimeric protein comprises 2, 3, 4, 5 or 6 genetically engineered mutant T. denticola FhbBs.
9. (currently amended) A vaccine composition comprising a recombinant protein of claim 1.
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/or use the invention commensurate in scope with these claims.
The specification states that substitutions, additions, or deletions may be made to the defined sequences; however, the specification provides no guidance as to what the nucleotides may be changed without causing a detrimental effect to the protein and its ability to protect or treat Streptococcus infection. While it is known that many amino acid substitutions are possible in any given protein, the position within the protein’s sequence where amino acid substitutions can be made with a reasonable expectation of success are limited. Other positions are critical to the protein’s structure/function relationship, e.g., such as various positions or regions directly involved in binding, catalysis in providing the correct three-dimensional spatial orientation of binding and catalytic sites. These regions can tolerate only very little or no substitutions. Selective point mutation to one key residue could eliminate the function of the polypeptide. It could eliminate its functional properties. If the range of decreased binding ability after single point mutation of a protein antigen varies, one could expect point mutations in the protein antigen to cause varying degrees of loss of protection/function, depending on the relative importance to the binding interaction of the altered residue. Alternatively, the combined effects of multiple changes, as instantly claimed, in an antigenic determinant could again result in loss of function. A protein having multiple antigenic sites, multiple point mutations, or accumulated point mutations at key residues could create a new antigen that is precipitously or progressively unrecognizable by any of the antibodies in the polyclonal pool. As stated above, Applicants have not shown the particular substitution and the result it produces. Applicants have provided no guidance to enable one of ordinary skill in the art how to determine, without undue experimentation, the effects of different amino substitutions and the nature and extent of the changes that can be made. It is expensive and time consuming to make amino acid substitutions at more than one position, in a particular region of the protein, in view of the many fold possibilities for change in structure and the uncertainty as to what utility will be possessed. See Mikayama et al. (Nov.1993. Proc.Natl.Acad.Sci. USA, vol. 90 : 10056-10060) which teaches that the three-dimensional structure of molecules is important for their biological function and even a single amino acid difference may account for markedly different biological activities. Amino acids owe their ‘significance’ to their inclusion in a pattern which is directly involved in recognition by, and binding to, the receptor and the significance of the particular amino acids and sequences for different amino acids cannot be predicted a priori, but must be determined from case to case by painstaking experimental study. The instant claims allow for substitutions with amino acids of vastly different properties and they do not recite the specific changes in the claims. The specification also does not enable a vaccine comprising these mutants. There are no working examples or any evidence provided to support this scope.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miller et al (ASM Journals. 6/23/2016, Vol. 84 (6): 1050-1054; provided by Applicants).
Miller et al. discloses a recombinant chimeric protein comprising at least one genetically engineered mutant Treponema denticola Factor H Binding Protein B (FhbB) which comprises at least one mutation compared to a wild type FhbB primary sequence, wherein the at least one mutation prevents binding of the genetically engineered mutant T denticola FhbB to Factor H (FH) (as demonstrated in the present study, Ab elicited against recombinant FhbB proteins can compete with FH for binding to FhbB and can block FH cleavage by T. denticola. See page 2056, right-hand column, second paragraph. It is taught that chimeric FhbB-based vaccine or therapeutic -FhbB Ab cocktail that is intended to restore complement regulation by inhibiting T. denticola growth will require the inclusion of each major FhbB type. See page 2056, right-hand column, second paragraph. Using gene deletion/inactivation mutants of FhbB and dentilisin in the murine abscess model, Miller demonstrate that both proteins contribute to maximal abscess formation. See page 2056, right-hand column, third paragraph. They teach that Ab elicited against recombinant FhbB proteins can compete with FH for binding to FhbB and can block FH cleavage by T. denticola. See page 2056, right-hand column, second paragraph; chimeric FhbB-based vaccine or therapeutic -FhbB Ab cocktail that is intended to restore complement regulation by inhibiting T. denticola growth will require the inclusion of each major FhbB type, Pg. 2056, right-hand column, second paragraph. Therefore, Miller et al anticipates claim 1 and 9. In instant claim 9, the term “vaccine” is an intended use only. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by O’Brier et al (Molecular Microbiology. 36(1): 50-57. 11/20/20; provided by Applicants).
O’Brier et al teach the development of an FhbB based chimeric vaccine that elicits antibodies that block Factor H binding and cleavage by Treponema denticola. O'Brier et al. teaches a recombinant chimeric Treponema denticola FhbB (a T. denticola FhbB based-vaccine antigen. Tetra (FhbB-ch4) chimerics were engineered, Abstract; recombinant proteins were produced, Pg. 52, right column, first paragraph) comprising at least one mutation compared to a wild type FhbB primary sequence (Genes encoding FhbB proteins with single or double site-directed amino acid mutations were designed, Pg. 52, left column, first paragraph), wherein the at least one mutation prevents binding of the genetically engineered mutant T denticola FhbB to Factor H (FH) (The rationale for introducing site-directed amino acid substitutions into the FhbB proteins was to prevent FH binding to the protein, Pg. 54, right column, final partial paragraph). O’Brier teaches both tera and pentavalent fhbB chimerics. On page 54, Results and Discussion 3.1, O’Brier teach that recombinant wild-type mutants FhB1, FhB2 and FhB3 (and divergent FhB3 variants) were produced.
Therefore, O’Brier et al anticipates claim 1 and 9. In instant claim 9, the term “vaccine” is an intended use only. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Allowable Subject Matter
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Status of Claims:
SEQ ID NOs: 6 and 7 are free of the prior art.
Correspondence regarding this application should be directed to Group Art Unit 1645. Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center located in Remsen. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15,1989). The Group 1645 Fax number is 571-273-8300 which is able to receive transmissions 24 hours/day, 7 days/week.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Daniel E. Kolker, can be reached on (571) 272-3181.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 2/4/26