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
Applicant’s election of claims 1-28 [sic]; note with the amendment dated 09/01/2026, there are only claims 1-26 for examination, and as species In claim 4: bacterium; In claim 7: methicillin-resistant Staphylococcus aureus (MRSA); In claim 10: lysozyme; In claim 11: the lysozyme is of C-type (from, for example human); In claim 17: the preferable oxazolidinone core structure; In claims 18: Tedizolid Phosphate; In claim 21: a walR inhibitor or antagonist; In claim 24: solutions; In claim 25: drop; without traverse in the reply filed on 09/01/2026 is acknowledged. Claims 1-26 are pending in this application; claims 1-26 and the elected species reading on the elected invention is now under consideration for examination.
Priority
Applicants’ claim for the benefit of priority under 35 U.S.C. 119(e) is acknowledged. This application claims the priority of Provisional Application 63/590,783 filed on 10/16/2023.
Information disclosure statement
The information disclosure statements (IDS) submitted on 09/01/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statement is considered and initialed by the examiner.
Specification-Objection
Non-Compliant Amendment
I. Please note that the present claim amendment dated 09/01/2026 is a non-compliant amendment, because claims 27-33 are cancelled; in the interest of compact prosecution, as this non-compliance appears to be an inadvertent error which does not preclude examination on the merits, the claim amendments dated 09/01/2026 are being entered. The applicant is informed that non-compliant amendments may not be entered in future office actions. Appropriate correction is required in response to this office action.
1893.01(a)(4) Claim Amendment (Filed With the U.S. Designated or Elected Office) [R-10.2019]
For the manner of making amendments and the required format, see the applicable U.S. regulations, in particular 37 CFR 1.121 and 1.125. One of the requirements for effectively amending claims in a national phase application is a complete listing of all claims ever presented, including the text of all pending and withdrawn claims. The status of every claim in such listing must be indicated after its claim number by one of the following identifiers in a parenthetical expression: (Original), (Currently Amended), (Canceled), (Withdrawn), (Previously Presented), (New), and (Not Entered). However, to prevent delays in prosecution, the Office may waive certain provisions of 37 CFR 1.121 and accept alternative status identifiers not specifically set forth in 37 CFR 1.121(c). Accordingly claim listings that include alternative status identifiers as set forth in MPEP § 714, subsection II.C, item (E) will be accepted if the amendment otherwise complies with 37 CFR 1.121. See MPEP § 714, subsection II.C, item (E) and Acceptance of Certain Non-Compliant Amendments Under 37 CFR 1.121(c), 1296 OG 27 (July 5, 2005).
All "currently amended" claims must include markings to indicate the changes made relative to the immediate prior version of the claims: underlining to indicate additions, strike-through or double brackets for deletions (see 37 CFR 1.121(c) for further details regarding the format of claim amendments). Applicants should note that, in an amendment to the claims filed in a national phase application, the status identifier "original" must be used for claims that had been presented on the international filing date and not modified or canceled. The status identifier "previously presented" must be used in any amendment submitted during the national phase for any claims added or modified under PCT Articles 19 or 34 in the international phase that were subsequently entered in the national phase. The status identifier "canceled" must be used in any amendment submitted during the national phase for any claims canceled under a PCT Article 19 or 34 amendment in the international phase and subsequently entered in the national phase.
Example 1: Original claims 1-10; Article 19/34 filed with claims 1-20 listed on the replacement sheet wherein claims 1-10 were unchanged and claims 11-20 were added; the status of the claims prior to any further amendment under 37 CFR 1.121 would be as follows: claims 1-10 as "original" and claims 11-20 as "previously presented."
Example 2: Original claims 1-10; Article 19/34 filed with claims 1-9 listed on the replacement sheet wherein claims 1-9 were unchanged and claim 10 was cancelled; the status of the claims prior to any further amendment under 37 CFR 1.121 would be as follows: claims 1-9 as "original" and claim 10 as "cancelled."
Example 3: Original claims 1-10; Article 19/34 filed with claims 1-9 listed on the replacement sheet wherein claim 1 was unchanged, claim 2 was cancelled and claims 3-10 were renumbered as claims 2-9; the status of the claims prior to any further amendment under 37 CFR 1.121 would be as follows: claim 1 as "original,", claims 2-9 as "previously presented" and claim 10 as "cancelled."
Example 4: Original claims 1-10; Article 19/34 filed with claims 1-10 listed on the replacement sheet wherein claims 1 and 3-10 were unchanged and claim 2 was cancelled; the status of the claims prior to any further amendment under 37 CFR 1.121 would be as follows: claims 1 and 3-10 as "original" and claim 2 as "cancelled."
Proposed amendments that are not submitted in compliance with the applicable regulations will not be entered. For example, the submission with the national phase documents of a revised set of claims, absent a preliminary amendment to the claims in compliance with 37 CFR 1.121(c), will not be effective to amend the claims of record in the application.
35 U.S.C. 112 Specification:
(e) REFERENCE IN MULTIPLE DEPENDENT FORM. — A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.
MULTIPLE DEPENDENT CLAIMS
II. Claim 22 and claims 23-26 depending therefrom are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 22-26 has not been further treated on the merits. Claims 22 and 26 depends from claims 1-21 and claims 22-25.
Specification-Objection/Sequence Compliance
III. Applicants’ are advised that the application is not in compliance with 37 CFR §§ 1.821-1.825. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR §§ 1.821-1.825. Specifically, applicants’ are required to comply with the sequence rules by inserting the sequence identification numbers of all sequences within the claims and/or specification. It is particularly noted that Figures 8A-8G and 13D of Drawings/specification recite many sequences, but applicants’ fail to provide the SEQ ID NO: (sequence identifiers) to all the sequences recited in the specification; i.e., nucleotides 10 (ten) or more and amino acids 4 (four) or more. Sequences must be referred to by their sequence identifiers, see particularly 37 CFR 1.821(d). If the sequences appearing in the specification do not have SEQ ID NO: assigned to them, then an amendment to the sequence listing will be required as well. There must not be any new matter submitted, therefore it is important to be careful to include only the sequences that are already disclosed in the current specification. Failure to correct the deficiency will be held a non-responsive to this Office action. Correction and clarification required.
Sequence Rules: The nucleic acid sequences presented requires having a sequence identifier. In order to comply with the sequence rules Applicants must identify the sequence by providing SEQ ID NO:, and where required provide a new version of the sequence listing and disk. Applicant must submit a CRF copy and paper copy of the Sequence Listing, a statement that the content of the paper and computer readable copies are the same and where applicable include no new matter as required by 37 C.F.R. j 1.821(e) or 1.821(9 or 1.821(g) or 1 .825(d), as well as an amendment directing its entry into the specification. Note: If the nucleic acid sequences are already part of the sequence listing and the CRF, Applicants may amend the specification by providing the appropriate SEQ ID NO: or provide the SEQ ID NO, to the legend of the figure(s). Applicant's cooperation is requested in correcting other unidentified sequences of which applicant may become aware of in the specification.
Claims Objections
Claim 21 is indefinite in the recitation of “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA”, for the following reasons. As taught in the specification and the prior art, the terms of “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” are B. subtilis gene(s) names which appear to encode proteins associated with the biosynthesis of teichoic acid (see Prunty et al., Mol. Micorbiol., 2018, Vol. 109(1): 23-40; reference not enclosed). However, as written, the terms appear to be generically used and not limited to a specific organism. While the gene nomenclature used may be appropriate for B. subtilis genes, the use of this nomenclature for genes encoding proteins of identical function in other organisms may not be accurate. As known in the art, genes encoding proteins of identical function in two different organisms may use different designations. For example, the ARO4 gene of Candida albicans encodes a DAHP synthase whereas the E. coli counterpart is the aroF gene. See the abstract of Sousa et al. (Microbiology 148(Pt5):1291-1303, 2002; reference not provided). As such, the use of gene terminology which is applicable to some organisms and not to others is confusing since the claims use this gene nomenclature with respect to any organism. In addition, the term of “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” is being used to refer to a proteins/enzymes. While this term would be appropriate for a B. subtilis protein encoded by the “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” genes, the term is confusing when the claims appear to be using this term generically and not limiting the source of the protein. Furthermore, since it is not expected that every bacterium would have “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” or that an equivalent operon would be present in every bacterium. For examination purposes, the “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” will be interpreted as “teichoic acid biosynthesis genes” when appropriate. Correction is required.
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. Claim 2, 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 applicant regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In the present instance, claim 2 recites the narrow recitation “at least a 10-fold…”, and the claims also recite “50-fold …900-fold…” which is the broader statement of the range/limitation (range within range). It is not clear what the applicants’ intend to encompass in the rejected claims and the metes and bounds of the claims are unclear and as being indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. Correction and clarification is required. Examiner suggests for the following “50-fold …900-fold…” applicants’ consider writing additional new claims as dependent claims from claim 2.
II. Claims 3-4, 6, 10 and 17, 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 applicant regards as the invention.
In the present instance, claims 3-4, 6, 10 and 17 recite the broad limitation “not higher than 0.5…oxazolidinone class antibiotic” and the claims 3-4, 6, 10 and 17 also recites “preferably…”not higher than 0.03…eperezolid phosphate (EP)” which is the narrower statement of the limitation and it is not clear what the applicants’ intend to encompass in the rejected claims and the metes and bounds of the claims are unclear and as being indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. Correction and clarification is required. Examiner suggests consider writing additional new claims as dependent claims.
III. Claims 10, 16, and 24, 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 applicant regards as the invention.
Regarding claims 10, 16, and 24, the term “or” for each selected from “enzyme…suspension, injection”, which is open claim language similar to using the term “group comprising” rather than “group consisting of’ in a Markush group claim. Also, the claim does not recite an “or” to indicate a closed group among the different “enzyme…suspension, injection”. For example, in claim 10, it is unclear whether the “ selected from the group consisting of lysozyme, an isoform and homologue thereof, lysin and lysostaphin; and preferably, the hydrolase is lysozyme or an isoform or homologue thereof” are listed in the alternative or in an open list. Thus the clams 10, 16, and 24 still unclear because it is unclear what specific structures are being claimed in a closed list of alternative species.
IV. Claim 11 is rejected under of 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 applicant regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In the present instance, claim 11 recites the broad limitation “lysozyme is of C-type…or bacterial-type” and the claim also recites “for example human or chicken…for example bacteria, such as Bacillus subtilis” which is the narrower statement of the range/limitation and it is not clear what the applicants’ intend to encompass and the metes and bounds of the claim is unclear and as being indefinite; it is unclear whether the limitation(s) following the phrase “for example” are part of the claimed invention. See MPEP § 2173.05(d). Clarification and correction is required.
V. Claim 13 and claims 14-15 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.
At the outset, patentability is not determined whether the drug is approved or not approved by any “drug authority” and hence no patentable weight is given to “drug approved by a local drug regulatory authority”. Claim 13 recites the phrase “drug approved by a local drug regulatory authority”; the phrase “drug approved by a local drug regulatory authority” in claim 13 renders the claim indefinite and considered to be a relative term which renders the claim indefinite and the specification does not provide a standard for ascertaining the “drug regulatory authority” or any other metric, and one of ordinary skill in the art would not be able to reasonably determine the metes and bounds, as “drug regulatory authority” (includes many undefined and unlimited drug authorities of unknown regulatory rules and regulations) and varies widely depending on the individual situation as well as the person making the determination and is dependent upon set of conditions defined by the individual situation. It is not clear to the examiner as to what “drug approved by a local drug regulatory authority” is encompassed in the above phrase Thus, the scope of the claim is unclear. A perusal of the specification does not provide any support for claim 13, as written “drug approved by a local drug regulatory authority” the specification does not recite the specific conditions/approved by a certain “drug authority”, the applicants' intend to encompass. Clarification and correction is required. For examination purposes no patentable weight is given to “drug approved by a local drug regulatory authority”.
VI. Claim 21 is indefinite in the recitation of “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA”, for the following reasons. As taught in the specification and the prior art, the terms of “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” are B. subtilis gene(s) names which appear to encode proteins associated with the biosynthesis of teichoic acid (see Prunty et al., Mol. Micorbiol., 2018, Vol. 109(1): 23-40). However, as written, the terms appear to be generically used and not limited to a specific organism. While the gene nomenclature used may be appropriate for B. subtilis genes, the use of this nomenclature for genes encoding proteins of identical function in other organisms may not be accurate. As known in the art, genes encoding proteins of identical function in two different organisms may use different designations. For example, the ARO4 gene of Candida albicans encodes a DAHP synthase whereas the E. coli counterpart is the aroF gene. See the abstract of Sousa et al. (Microbiology 148(Pt5):1291-1303, 2002; reference not provided). As such, the use of gene terminology which is applicable to some organisms and not to others is confusing since the claims use this gene nomenclature with respect to any organism. In addition, the term of “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” is being used to refer to a proteins/enzymes. While this term would be appropriate for a B. subtilis protein encoded by the “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” genes, the term is confusing when the claims appear to be using this term generically and not limiting the source of the protein. Furthermore, since it is not expected that every bacterium would have “TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” or that an equivalent operon would be present in every bacterium. For examination purposes, the “walR… LTA/WTA… TarA, TarB, TarD, TarF, TarL, TarS, TagH and FmtA” will be interpreted as “teichoic acid biosynthesis genes” when appropriate. Correction is required.
VII. Claims 22-26 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 22-26 as being in improper form because multiple dependent claims; it is not clear what the applicants’ intend to encompass in the rejected claims and the metes and bounds of the claims are unclear and as being indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. Correction and clarification is required.
Claim rejections: 35 U.S.C. 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14-15 recites “…local drug regulatory authority is the FDA in the USA, EMA in EP, PMDA in JP, or NMPA in CN” and depends from claim 13; and does not further limit claim 13.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of pre-AIA 35 U.S.C. 112, 4th paragraph, are related to matters of form, non-compliance with pre-AIA 35 U.S.C. 112, 4th paragraph, renders the claim unpatentable just as non-compliance with other paragraphs of 35 U.S.C. 112 would. See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92, 79 USPQ2d 1583, 1589-90 (Fed. Cir. 2006) (holding a dependent claim in a patent invalid for failure to comply with pre-AIA 35 U.S.C. 112, 4th paragraph). Therefore, if a dependent claim does not comply with the requirements of 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, the dependent claim should be rejected under pre-AIA 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as unpatentable rather than objecting to the claim. See also MPEP § 608.01(n),subsection III, “Infringement Test” for dependent claims.
Claim Rejections: 35 USC § 112(a)
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 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
I. Claims 1-26 are rejected under 35 U.S.C. (a) or 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 26-45 of the instant application as interpreted are directed to a genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti- microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation).
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “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”. As indicated in MPEP § 2163, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that 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.
In the instant case, there is no structure associated with function with regard to the members of the genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (as in claims 1-25; and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation).
No information, beyond the characterization of a specific composition comprising lysozyme enzyme and antibiotic auranofin combination effective against methicillin-resistant S. aureus or S. epidermis (see Examples 1-2, pages 26-56 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed members of the genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation).
The genus of polypeptides and the anti-microorganism drugs required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited a specific composition comprising lysozyme enzyme and antibiotic auranofin combination effective against methicillin-resistant S. aureus or S. epidermis (see Example 1-2, pages 26-56 of specification), since one could use structural homology to isolate or identify those polypeptides with the desired activity 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 and the art also teaches, even highly structurally homologous polypeptides do not necessarily share the same function and conversely functionally similar molecules do not necessarily have similar structures. For example proteins having similar structure have different activities; 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. Similarly, Wishart et al., (J. Biol. Chem., 1995, Vol. 270(10): 26782-26785) teach that a single mutation converts a novel phosphotyrosine binding domain into a dual-specificity phosphatase. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated above, no information beyond the characterization of a specific composition comprising lysozyme enzyme and antibiotic auranofin combination effective against methicillin-resistant S. aureus or S. epidermis (see Examples 1-2, pages 26-56 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation). As the claimed genera of polypeptides having widely variable structure and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant/homologs) 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. (a) or 35 U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Enablement
II. Claims 1-26 are rejected under 35 U.S.C. (a) or 35 U.S.C. 112, first paragraph, because the specification is enabling for the characterization of characterization of a specific composition comprising lysozyme enzyme and antibiotic auranofin combination effective against methicillin-resistant S. aureus or S. epidermis (see Examples 1-2, pages 26-56 of specification). However, specification does not reasonably provide enablement for members of the genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above 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 1-26 are so broad as to encompass: genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti- microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above 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 polypeptides and anti-microorganism drugs 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 of a specific composition comprising lysozyme enzyme and antibiotic auranofin combination effective against methicillin-resistant S. aureus or S. epidermis (see Examples 1-2, pages 26-56 of specification). It would require undue experimentation of the skilled artisan to make and use the claimed polypeptides and the encoding polynucleotides i.e., members of the genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (as in claims 1-25); and a kit comprising said genus of undefined and unlimited structures (as in claim 26; also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation). The specification provides no guidance with regard to the making of variants and mutants or with regard to other uses as claimed in the instant claims. 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), 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 and the encoding polynucleotides encompassed by these claims.
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: genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures and a kit comprising said genus of undefined and unlimited structures (also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation), as claimed in claims 1-26, because the specification does not establish: (A) a rational and predictable scheme for identifying an enzyme of undefined and unlimited structural features exhibiting desired activity and with an expectation of obtaining the desired biological function; (B) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptides; (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.
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 polypeptides/enzymes with an enormous number of modifications in the claimed method and kit. 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).
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-16 and 22-24 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Schuch et al., (JID., 2014, Vol. 209: 1469-1478), when given the broadest reasonable interpretation.
Claims 1-16 and 22-24 as interpreted are directed to genus of undefined and unlimited structures i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures (also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation).
Schuch et al., (JID., 2014, Vol. 209: 1469-1478), regarding claims 1-2, 4-16 and 22-24 disclose a combination therapy with Lysin CF-301/hydrolase/enzyme and antibiotics such as Daptomycin, Vancomycin and Linezolid and is superior to antibiotic alone for treating Methicillin-Resistant (MRSA) Staphylococcus aureus strains induced murine bacteremia (see Abstract; Methods, col. 2, page 1470 to cols. 1-2, page 1471; Fig. 2, page 1472; Fig. 3, page 1473; Fig. 5, page 1476; and entire document); Schuch et al., regarding claims 2-3, disclose assays involving fractional inhibitory concentration index (FICI) value of the combination is less than <0.5 (col. 2, page 1474; Fig. 4, page 1474) and a synergistic, at least 128-fold decrease in the amount of Daptomycin required to inhibit growth (col. 1, page 1475; and Discussion).
Hence, Schuch et al., (JID., 2014, Vol. 209: 1469-1478) is deemed to anticipate claims 1-16 and 22-24 of the instant application, when given the broadest reasonable interpretation.
Since the Office does not have the facilities for examining and comparing applicants’ composition of the instant invention with composition of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed composition of the instant invention and the composition of the prior art (i.e., that the composition of the prior art does not possess the same material structural and functional characteristics of the composition of the instant invention). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
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.
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 1-26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Schuch et al., (JID., 2014, Vol. 209: 1469-1478) as applied to claims 1-16 and 22-24 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and in view of Yang et al., J. Control. Release., 2021, Vol. 329: 454-457), Li et al., (CN1557485A; see provided English Machine Translation), Delost et al., (J. Med. Chem., 2018, Vol. 16: 10996-11020), Kalam et al., (Pharmaceuticals., 2022, et al., Vol. 14, 1328, pages 1-27), Gonzalez et al., (Future Med. Chem., 2018, Vol. 10(5): 541-560) and Sharma et al., (US 2017/0136102 A1).
The disclosure of Schuch et al., (JID., 2014, Vol. 209: 1469-1478) as applied to claims 1-16 and 22-24 is described above in 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above. However, Schuch et al., is silent regarding elected species, wherein the hydrolase is lysozyme (as in claims 10-11); wherein anti-microorganism drug is selected from an oxazolidinone (as in claim 17); said anti-microorganism drug is Tedizolid Phosphate (as in claims 18-20); a kit comprising said combination of one or more enzymes and one or more anti-microorganism drugs (as in claim 26).
Regarding claims 1-16 and 22-24, Yang et al., J. Control. Release., 2021, Vol. 329: 454-457) also teach and disclose eradicating intracellular MRSA Staphylococcus sp., via targeted delivery of lysostaphin/enzyme and vancomycin/antibiotic with mannose-modified exosomes (Abstract; Fig. 1, page 455; Fig. 7-13, pages 461-466; and entire document).
Regarding elected species in claims 10-11 and 17-20, the following references teaches the structural and functional elements of the instant invention:
Regarding claims 10-11, Li et al., (CN1557485A; see provided English Machine Translation), teach a therapeutic composition comprising human lysozyme and antibiotics clarithromycin, roxithromycin, amoxicillin, vancomycin and decomycin (page 15) in the form a solution/drop form of the instant invention (Claims; Summary of the invention, pages 6-8).
Regarding claims 17-20, references (i) Delost et al., (J. Med. Chem., 2018, Vol. 16: 10996-11020), and (ii) Kalam et al., (Pharmaceuticals., 2022, et al., Vol. 14, 1328, pages 1-27), wherein anti-microorganism drug is selected from an oxazolidinone, FDA approved, see Delost et al., Fig. 3, page 10997; Fig. 16, page 11005; said anti-microorganism drug is Tedizolid Phosphate, Kalam et al., advantageously teach the use of Tedizolid Phosphate for topical ocular applications as solution/drop, see Abstract; ¶ 3.10, & Fig. 8, page 19; Fig. 9, page 20; and entire document.
Regarding claim 21, wherein the combination further comprises an walR inhibitor or antagonist, Gonzalez et al., (Future Med. Chem., 2018, Vol. 10(5): 541-560) provide teaching, suggestion and motivation and advantageously teach that the transcriptional regulators like walR are valuable targets for novel antibacterial strategies (see pages 552-553); “WalR inhibitors, walrycin A (4-methoxy-1-naphthol) (Figure 4D; page 550) and walrycin B (1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-dione) (Figure 4D; page 550). Both compounds showed antimicrobial activity against B. subtilis and S. aureus, though walrycin B appeared more effective in killing both bacteria, with MIC values of 0.39 and 3.13 μg/ml, respectively. Both WalR inhibitors sensibly affected the expression of WalR target genes in vivo”.
Regarding claim 26, analogous art Sharma et al., (US 2017/0136102 A1) (¶ [0134]) teach pharmaceutical compositions comprising at least one outer membrane acting biologic/Lysin B/enzyme with the chemotherapeutic(s), e.g., an esterase, lipase, cutinase, or α/β hydrolase, provided in a pharmaceutically acceptable excipient; e.g., a cocktail mixture of biologics that collectively increase the permeability of the outer membrane of the target mycobacteria, of the macrophage, and/or the fibroblasts sequestering the granuloma. In this manner, the presently disclosed compositions of can be tailored to the needs of the patient sterile (¶ [0134]) and in the form a Kit (see Claims 15-18; and entire document) and thus providing teaching, suggestion and motivation to include the composition in a ready to use Kit form.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine and modify the teachings of Schuch et al., or Yang et al., and employ the lysozyme and antibiotics oxazolidinone, Tedizolid Phosphate, and an walR inhibitor or antagonist structural and functional elements, as claimed in the instant invention and as taught in the references of Li et al., Delost et al., Kalam et al., Gonzalez et al., and in the form of a Kit as suggested by Sharma et al., and to produce the same in a Kit form. Motivation to generate such a Kit derives from the fact that combination of one or more enzymes and one or more anti-microorganism drugs is a commercial product of importance and useful in the preparation of drug compositions in the pharmaceuticals industry (Schuch et al., Yang et al., and Kalam et al.,). The expectation of success is high, because the combined teachings of Schuch et al., or Yang et al., Li et al., Delost et al., Kalam et al., Gonzalez et al., and Sharma et al., teach combination of one or more enzymes and one or more anti-microorganism drugs and said references also provide the structural and functional elements of the instant invention (Teaching, Suggestion and Motivation).
Given this extensive teaching in prior art (Schuch et al., or Yang et al., Li et al., Delost et al., Kalam et al., Gonzalez et al., and Sharma et al.,) i.e., combination of one or more enzymes of undefined unlimited structures including variants, mutants and homologs and one or more anti-microorganism drugs of undefined and unlimited structures and a kit comprising said genus of undefined and unlimited structures (also see claims objections; 35 U.S.C. 112(b) and 35 U.S.C. 112(d) rejections above for claims interpretation), as claimed in claims 1-26 is not of innovation but of ordinary skill in the art and the expectation of success is extremely high i.e., “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at, 82 USPQ2d at 1397”.
Therefore, claims 1-26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Schuch et al., (JID., 2014, Vol. 209: 1469-1478) as applied to claims 1-16 and 22-24 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and in view of Yang et al., J. Control. Release., 2021, Vol. 329: 454-457), Li et al., (CN1557485A; see provided English Machine Translation), Delost et al., (J. Med. Chem., 2018, Vol. 16: 10996-11020), Kalam et al., (Pharmaceuticals., 2022, et al., Vol. 14, 1328, pages 1-27), Gonzalez et al., (Future Med. Chem., 2018, Vol. 10(5): 541-560) and Sharma et al., (US 2017/0136102 A1).
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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