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 .
Detailed Action
Amended Claims 1-10 (dated 06/11/2025) are pending and now under consideration.
Priority
Acknowledgment is made of applicants’ claim for foreign priority under 35 U.S.C. 119(a)-(d). This application is a 371 of PCT/JP2023/016830 filed on 04/28/2023 and claims the priority date of Japan application 2022-074458 filed on 04/28/2022; however, no English translation of said foreign priority application has been provided. Therefore, the priority date for instant claims under consideration is deemed to be the filing date of 371 of PCT/JP2023/016830 filed on 04/28/2023.
Information disclosure statement
The information disclosure statement (IDS) submitted on 11/15/2024, 05/21/2026 and 05/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statements are considered and initialed by the examiner.
Claims Objections
I. Claim 1 and claims 2-10 depending therefrom are objected; recitation of “and/or” in claims 1 and 3 makes the claim indefinite, as it is not clear what limitations must be present. Correction and clarification is required. Examiner suggests amending the claims to recite “…or …”.
II. Claim 3 is objected to, due to the following informality: Claim 3 recites the term “…a base sequence...”, examiner suggests amending the claim to recite “…polynucleotide sequence...”.
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.
I. Claims 1-4 and claims 5-10 depending therefrom 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.
Regarding claims 1-4, “A lytic agent…” is a limitation that invokes 35 U.S.C. 112(f) or 35 U.S.C. 112 (pre-AIA ), sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for the claimed function. “A lytic agent…” is non-structural term and the scope of the term in claims 1-4 is indefinite.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or 35 U.S.C. 112 (pre-AIA ), sixth paragraph; or
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the claimed function, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
For examination purposes claims 1-10 are interpreted to encompass “lytic enzyme/polypeptide, encoding polynucleotide”; furthermore no patentable weight is given to the preamble “A lytic agent for Enterococcus faecalis…”, as rejected claims 1-10 are considered to be “method of use of the product” claims and therefore, patentable weight is given only to the claimed product and not to the method of use.
II. Claim 1 and claims 2-10 depending therefrom 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; recitation of “and/or” in claims 1 and 3 makes the claims indefinite, as it is not clear what limitations must be present. The metes and bounds of claims 1 and 3 is not clear and thus, it would not be possible to one of ordinary skill in the art to define the metes and bounds of the desired patent protection. The rejection may be overcome by amending the claims to recite “… or …”. Correction and clarification is required. Examiner suggests amending the claim to recite “…or …”.
III. Claim 1 and claims 2-10 depending therefrom 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 and 3 recites the phrase “amino acid sequence shown in SEQ ID NO: 1; …“a base sequence shown in SEQ ID NO: 2”. The metes and bounds of the term “shown in” is not clear in the context of the claims. It is not clear to the examiner if the recited amino acid sequence has the amino acid sequence of SEQ ID NO: 1? and the recited polynucleotide sequence has the nucleic acid sequence of SEQ ID NO: 2? or is a representative member of a genus/merely exemplary. Examiner suggests amending the claim to make a direct reference to SEQ ID NO: 1 and SEQ ID NO: 2. Clarification and correction required.
IV. Claim 3 is 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.
Claim 3 is rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention. Claim 3 recites the phrase “… hybridizes… under a high stringency condition”, but does not recite the conditions under which the hybridization must occur. In the art what is considered “…high stringency condition” varies widely depending on the individual situation as well as the person making the determination and nucleic acids which hybridize under one set of conditions and having partial complementarity to a target sequence may not hybridize under other conditions. It is not clear to the examiner as to what type of stringency hybridization conditions and percentage of identity of the complementary polynucleotide sequence that is hybridizing to the target sequence are encompassed in the above phrase. Thus, the scope of the claim is unclear. A perusal of the specification for hybridization conditions as written does not recite the specific conditions the applicants' intend to encompass. As such it is unclear how homologous to the amino caid sequence of SEQ ID NO: 1 and the encoding polynucleotide sequence SEQ ID NO: 2, a sequence of interest must be to be included within the scope of the claim. Clarification and 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):
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.
Written-description
Claims 1-10 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 purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“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 . . ., reduction to drawings . . ., or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus.” MPEP 2163.
Furthermore, 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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163.
The claims recite the following broadly claimed genera: Claims 1-10 recite a genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation).
As described, claims 1-10 encompasses any lytic enzyme with no structural limitations, including wild-type enzymes and enzymes heavily mutated from known wild-type enzymes, with the sole functional proviso being that “lytic agent”. The structural elements recited in claims 1-10 are not sufficient structure to form a “lytic agent … lytic enzyme” having no specific structural elements of any kind and having associated function. Therein, inherent unpredictability in regards to which amino acid sequences may have the associated function i.e., “lytic agent … lytic enzyme” activity and possibly fall within the claims and those amino acid sequences that do not have “lytic agent … lytic enzyme” activity. As such, claims 1-10 recite a genera of biomolecules, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.” Further, without any structural limitations for structural features that actually provide for “lytic agent … lytic enzyme” activity, claims 1-10 have no defined outer bounds for the scope of “lytic agent … lytic enzyme” that fall within the scope of the claims. Due to the literal unlimited structural scope of the claims, it is not possible to provide for a representative number of species that adequately described are representative of the entire genus having no fixed structural outer boundaries. Further, such genera of altered enzymes as recited lack “a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials” and without any required structure that is sufficient for providing the recited enzyme activity, the recited genera lack disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. The claims lack adequate written description in the as-filed specification for the reasons stated.
No information, beyond the characterization specific structures having the amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2 and a method of use, has been provided by the applicants’, which would indicate that they had possession of the claimed genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation).
The genus of polypeptides and the encoding polynucleotides required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structures and the characterization of the amino acid sequences of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2, since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”: (a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105).
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340) also highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity. Seffernick et al., (J. Bacteriol. 183(8): 2405-2410, 2001), teaches that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Broun et al., (Science 282:1315-1317, 1998), teaches that as few as four amino acid substitutions can convert an oleate 12-desaturase into a hydrolase and as few as six amino acid substitutions can transform a hydrolase to a desaturase.
As stated above, no information beyond the characterization specific structures having the amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2 and a method of use, has been provided by the applicants’, which would indicate that they had possession of the claimed genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation). As the claimed genera of polypeptides and encoding polynucleotides having widely variable structures and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant) correlating structure with function has been provided. Furthermore, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features” (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Enablement
Claims 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification is enabling for the characterization specific structures having the amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2 and a method of use. However, specification does not reasonably provide enablement for a genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation). 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.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claims 1-10 are so broad as to encompass: a genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation). The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polynucleotides and encoded polypeptides broadly encompassed by the claims. Since the amino acid sequence of a protein encoded by a polynucleotide determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence and the respective codons in its polynucleotide, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the encoded proteins' structure relates to its function. However, in this case the disclosure is limited to the characterization specific structures having the amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2 and a method of use. It would require undue experimentation of the skilled artisan to make and use the claimed polypeptides/enzymes, a genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation). The specification but provides no guidance with regard to the making of variants and mutants or with regard to other uses. In view of the great breadth of the claims, amount of experimentation required to make and use the claimed polypeptides, the lack of guidance, working examples, and unpredictability of the art in predicting function from a polypeptide primary structure (for example, see Whisstock et al., Prediction of protein function from protein sequence and structure. Q Rev Biophys. 2003, Aug. 36 (3): 307-340. Review), the claimed invention would require undue experimentation. As such, the specification fails to teach one of ordinary skill how to use the full scope of the polypeptides/enzymes encompassed by the claims. However, claims reading on significant numbers of inoperative embodiments would render claims non-enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.” Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298, 302 (CCPA 1971); MPEP 2164.08(b). Here, the claims read on a significant number of inoperative embodiments. While enzyme isolation techniques, recombinant and mutagenesis techniques are known, and it is not routine in the art to screen for multiple substitutions or multiple modifications as encompassed by the instant claims, the specific amino acid positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass: a genera of lytic agent(s), i.e., a lytic enzyme comprising any of the amino acid sequences of the following (a) to (c) or an active fragment thereof: … an amino acid sequence in which one or multiple amino acids are added, deleted, and/or substituted in the amino acid sequence shown in SEQ ID NO: 1 of unlimited and undefined structures and any fragment/subsequence within SEQ ID NO: 1; a polynucleotide encoding the lytic enzyme or an active fragment thereof of… a base sequence in which one or multiple bases are added, deleted, and/or substituted in the base sequence shown in SEQ ID NO: 2; a base sequence which hybridizes with the base sequence complementary to the base sequence shown in SEQ ID NO: 2 under a high-stringent condition, any polynucleotide sequence that “hybridizes under any undefined stringent conditions” and having any sequence identity to SEQ ID NO: 2 and encoding any polypeptide having any sequence identity to SEQ ID NO: 1 of undefined and unlimited structures (also see claims objections, and 35 U.S.C. 112(b) for claims interpretation), because the specification does not establish: (A) a rational and predictable scheme for modifying specific amino acid residues and having no specific structural elements and an expectation of obtaining the desired biological/biochemical function; (B) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptide; (C) the tertiary structure of the molecule and folding patterns that are essential for the desired activity and tolerance to modifications; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
While as discussed above, the specification provides guidance with regard to the characterization specific structures having the amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotide comprising the sequence of SEQ ID NO: 2 and a method of use, however, the scope of claims 1-10 is so broad and the lack of guidance either in the specification or in the prior art, the claims remains not commensurate in scope with the enabled invention and therefore for the rejected claims, this would clearly constitute undue experimentation. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed (guided mutants). Such guidance has not been provided in the instant specification or in the prior art. The art also teaches the following regarding complexity of the structure/function relationship: The reference of Chica et al., (Curr. Opin. Biotechnol., 2005, Vol. 16: 378-384) teaches that the complexity of the structure/function relationship in enzymes has proven to be the factor limiting the general application of rational enzyme modification and design, where rational enzyme modification and design requires in-depth understanding of structure/function relationships. The reference of Sen et al., (Appl. Biochem. Biotechnol., 2007, Vol.143: 212-223), teaches in vitro recombination techniques such as DNA shuffling, staggered extension process (STEP), random chimera genesis on transient templates (RACHITT), iterative truncation for the creation of hybrid enzymes (ITCHY), recombined extension on truncated templates (RETT), and so on have been developed to mimic and accelerate nature's recombination strategy. However, such rational design and directed evolution techniques only provide guidance for searching and screening for the claimed polypeptide which is not guidance for making and/or using the claimed polypeptide.
Thus, applicants’ have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including polynucleotides and encoded polypeptides with an enormous number of modifications. The scope of the claim must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1975)). Without sufficient guidance, determination of polypeptides/enzymes having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Although the claims are examined in the light of the specification, specification cannot be read into the claims, i.e., the limitations of the specification cannot be read into the claims (see MPEP 2111 R-5).
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
Claims 1-3 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 1-3 are directed to a law of nature or a natural phenomenon. Claims 1-3 as interpreted are directed to polypeptides comprising the amino acid sequences SEQ ID NO: 1 and encoding polynucleotide of SEQ ID NO: 2 (For examination purposes claims 1-3 are interpreted to encompass “endolysin polypeptide and encoding polynucleotide”; furthermore no patentable weight is given to the preamble “A lytic agent for Enterococcus faecalis…”, as rejected in claims 1-3 are considered to be “method of use of the product” claims and therefore, patentable weight is given only to the claimed product and not to the method of use; see 35 U.S.C. 112(b) rejection above). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons stated below.
The “2014 Interim Guidance on Patent Subject Matter Eligibility” 79 FR 74618 (Dec. 16, 2014) directs that claims drawn to 1) a composition of matter, 2) a law of nature or a natural phenomenon and 3) lacking recitation of additional elements that make the claims directed to significantly more than a judicial exception are ineligible for patenting under 35 U.S.C. 101. See, 79 FR, page 74621 (flow chart). Nature-based compositions of matter are not directed to significantly more than a judicial exception when the claimed "naturally occurring products and some man-made products ... are essentially no different from a naturally occurring product ... that fall under the laws of nature or natural phenomena exception.” 79 FR, page 74623, left column. That is, a patent-eligible composition of matter must be "markedly different" in terms of the "product's structure, function, and/or other properties." 79 FR, page 74623, center column. Further, processes directly to isolating nature-based compositions of matter have also been found to be directed to nothing more than a judicial exception when only routine purification techniques are employed. 79 FR, page 74622, center column (e.g. isolating DNA or other nature-based products).
Here, naturally-occurring polypeptide comprising the amino acid sequence of SEQ ID NO: 1 and annotated as endolysin are disclosed in the following references: (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4 having 100% sequence identity to SEQ ID NO: 1 of the instant application and the encoding polynucleotide; and (ii) GenBank Accesion#RYU34564.1 having 100% sequence identity to SEQ ID NO: 1 and the encoding polynucleotide of the instant application (see provided sequence alignments). The features of claims 1-3 is met by the reference polypeptides and the encoding polynucleotides in the disclosed references above. Since the features of the claims are met by the structure of a polypeptide of SEQ ID NO: 1 and the encoding polynucleotide of the instant application and the claims do not recite additional features or elements that amount to significantly more than the judicial exception, since the structure recited in claims 1-3 is "essentially no different from a naturally occurring product” such that there is no marked difference in the product's structure, function, and/or other properties. As such, the claims 1-3 recite patent ineligible subject matter for the reasons stated.
Claim Rejections: 35 USC § 102 (AIA )
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.
I. Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by comprising the amino acid sequence of SEQ ID NO: 1 and annotated as endolysin are disclosed in the following references: (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4 having 100% sequence identity to SEQ ID NO: 1 of the instant application and the encoding polynucleotide; and (ii) GenBank Accesion#RYU34564.1 having 100% sequence identity to SEQ ID NO: 1 and the encoding polynucleotide of the instant application (see provided sequence alignments).
II. Claims 1-5 and 8-10 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Doucette-Stamm et al., (US 6,617,156, in IDS).
Doucette-Stamm et al., (US 6,617,156, in IDS) disclose a reference polypeptide comprising the amino acid sequence having 99.5% sequence identity to SEQ ID NO: 1 and annotated as endolysin and the encoding reference polynucleotide having 99.8% sequence identity to SEQ ID NO: 2 of the instant application (see provided sequence alignments). Doucette-Stamm et al., also disclose expression vectors comprising the encoding polynucleotide and method of making the polypeptide (col 10, lines 65-67 to col. 15, lines 1-48); pharmaceutical formulations suitable of antibacterial therapy in pharmaceutically acceptable carriers and useful for treating E. faecalis infections (col. 44, lines 47-67 to col. 45, lines 1-47); and carrier systems as enteric-coated capsules and polylactide-glycolide microspheres (col. 39, lines 35-42); said reference discloses E. faecalis infection treatment methods and to incorporate a therapeutically effective amount of an antibacterial agent or composition; the prophylactically and/or therapeutically effective amounts can be administered in one administration or over repeated administrations; the antibacterial agents and compositions can be administered topically or systemically; systemic administration includes both oral and parental routes. Parental routes include, without limitation, subcutaneous, intramuscular, intraperitoneal, intravenous, transdermal, inhalation and intranasal administration (col. 45, lines 30-47).
Hence, Doucette-Stamm et al., (US 6,617,156, in IDS) is deemed to anticipate claims 1-5 and 8-10 as written and when given the broadest reasonable interpretation.
Claim Rejections: 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10 are rejected under 35 U.S.C. 103(a) as being unpatentable over : (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4 having 100% sequence identity to SEQ ID NO: 1 of the instant application and the encoding polynucleotide; and (ii) GenBank Accesion#RYU34564.1 having 100% sequence identity to SEQ ID NO: 1 and the encoding polynucleotide of the instant application (see provided sequence alignments) as applied to claims 1-3 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above); and Doucette-Stamm et al., (US 6,617,156, in IDS) as applied to claims 1-5 and 8-10 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and further in view of Yoong et al., (US 2007/0025978 A1) and Pinto et al., (FEMS Microbiol Rev., fuab19, 2021, Vol. 45: 1-29).
The disclosure of (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4 and (ii) GenBank Accesion#RYU34564.1 as applied to claims 1-3 is described above; and Doucette-Stamm et al., (US 6,617,156) as applied to claims 1-5 and 8-10 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2). However, (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4; (ii) GenBank Accesion#RYU34564.1; and Doucette-Stamm et al., (US 6,617,156, in IDS) are silent regarding wherein said enterococcal infection is intestinal dysbiosis, vancomycin-resistant enterococcus bacteremia, or infective endocarditis (as in claim 6); and wherein said intestinal dysbiosis is graft-versus-host disease or alcoholic liver disease (as in claim 7).
Regarding claims 6-7, Yoong et al., (US 2007/0025978 A1) provide teaching, suggestion and motivation for the choice of therapeutic composition comprising a bacteriophage lysin having lytic killing activity against one or more bacteria, including Enterococcus faecalis vancomycin resistant strains (see Abstract; and entire document); Yoong et al., disclose Enterococcus faecalis and nosocomial infections of enterococci account for bacteremia, surgical wound infections, urinary tract infections, and of endocarditis cases (¶ [0003]) and therapeutic compositions comprising bacteriophage lysin (¶ [0175-0180]).
Regarding claims 6-7, Pinto et al., (FEMS Microbiol Rev., fuab19, 2021, Vol. 45: 1-29) also provides teaching, suggestion and motivation to a skilled artisan regrading compositions comprising encapsulated lysins for the treatment of infections due to Enterococci and various routes of administration (Abstract; col. 1, page 4; col. 1-2; Table 2, page 10; page 16; and entire document)
As such, disclosure of strategy and methods for treatment of enterococcal infections with compositions comprising lytic phage lysins, as in claims 5-10 of the instant invention, such as that of references of Yoong et al., and Pinto et al., teaching the advantages of said modifications, clearly suggests to a skilled artisan to modify the teachings of i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4; (ii) GenBank Accesion#RYU34564.1; and Doucette-Stamm et al., (US 6,617,156) and incorporate the structural and functional elements of Yoong et al., and Pinto et al., in the claimed method and pharmaceutical compositions for treatment of enterococcal infections under various clinical setting with compositions comprising lytic phage lysins as claimed in the instant invention. One of ordinary skill in the art would have a reasonable expectation of success, since the methods and pharmaceutical compositions for treatment of enterococcal infections with compositions comprising lytic phage lysins are well known in the art.
Therefore, claims 1-10 are rejected under 35 U.S.C. 103(a) as being unpatentable over : (i) UniProtKB/TrEMBL Accesion#A0A2S7M3H4 having 100% sequence identity to SEQ ID NO: 1 of the instant application and the encoding polynucleotide; and (ii) GenBank Accesion#RYU34564.1 having 100% sequence identity to SEQ ID NO: 1 and the encoding polynucleotide of the instant application (see provided sequence alignments) as applied to claims 1-3 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above); and Doucette-Stamm et al., (US 6,617,156, in IDS) as applied to claims 1-5 and 8-10 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and further in view of Yoong et al., (US 2007/0025978 A1) and Pinto et al., (FEMS Microbiol Rev., fuab19, 2021, Vol. 45: 1-29).
Allowable Subject Matter/Conclusion
None of the claims are allowable.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652
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