DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is Continuation-In-Part of International Application PCT/IL2021/051485, filed 12/14/2021, which in turns claims domestic benefit to US Provisional Application 63/126,277. Applicant’s claim for the benefit of a prior-filed provisional application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
The subject matter in the pending claims appears to be supported by the disclosures of the previously filed provisional application. Applicant should indicate if any future amendments introduce subject matter not previously disclosed in PCT/IL2021/051485 or 63/126,277.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed 6/16/2023 fails to fully comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.
The following references have not been considered because either no English language translation, or no copy of the reference has been provided:
Efremenko et al., RU-2016148169 (no English language translation was provided);
Barad et al., "A penicillium expansum glucose oxidase-encoding gene, GOX2, is essential for gluconic acid production and acidification during colonization of deciduous fruit". Molecular plant-microbe interactions 25, pp. 779-788. (2012);
Barad et al., "Accumulation of the mycotoxin patulin in the presence of gluconic acid contributes to pathogenicity of penicillium expansum". Molecular plant-microbe interactions 27, pp.66-77. (2014);
Ianiri et al, "Searching for genes responsible for patulin degradation in a biocontrol yeast provides insight into the basis for resistance to this mycotoxin". Applied and environmental microbiology 79, pp. 3101-3115. (2013).
A copy of the signed IDS has been placed in the application file, and the references identified above have not been considered, unless cited by the Examiner on a PTO-892.
Additionally, the reference Jami et al; "The penicillium chrysogenum extracellular proteome. Conversion from a food-rotting strain to a versatile cell factory for white biotechnology". Molecular & Cellular Proteomics 9, pp.2729-2744. (2010) has been cited twice in duplicate on the IDS filed 6/16/2023. This reference has been considered.
Drawings
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. In the instant case, FIG. 3 contains multiple amino acid sequences without proper identification of the sequences by use of an identifier.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at [0094]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Election/Restrictions
Applicant’s election without traverse of species 1iii of a phosphotriesterase-like lactonase having at least 30% identity (amended in the present claims to 90% sequence identity) to the wild-type PPH of M. tuberculosis (SEQ ID NO: 1) and of the species 2i corresponding to a G59 mutation in SEQ ID NO:1, in the reply filed on 7/21/2026 is acknowledged.
The election is herein made FINAL.
Response to Amendment
Applicant’s amendment to the claims filed 7/21/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 1-4, 7-10, 12-18, 22-24, and 26 are pending and have been examined on the merits.
Claim Interpretation
The disclosure refers to both “G59” and “G55”. The specification, at [0026], states that: “For clarity, the position of the amino acid residues in the sequences of the fusion-proteins used in the Examples section below, G55, corresponds to G59 in the isolated wild-type full length protein. Similarly, the sequence of the functionally active deletion mutant used to solve the three- dimensional structure of the phosphotriesterase-like lactonase from M. tuberculosis lacks the four first N-terminal amino acid residues (Zhang et al., 2019). Consequently, glycine at position 55 in the enzyme characterized in this specification corresponds to G59 according to the system used to identify amino acid residue positions in the enzymes of the present invention” .
Thus, it appears that the applicant is attempted to redefine “G55” as “G59”. It appears that only “G59” has been used in the claims. For the purpose of examining and searching, both G59 and G55 will be considered as suitable mutation positions, as determined from the B.R.I. in light of the claims, in light of the specification.
Claim Objections
Claim 1 is objected to because of the following informalities:
The term “M. tuberclorosis”, which should be spelled “M. tuberculosis”, is recited in line 8 of claim 1.
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.
Claims 1-4, 7-10, 12-18, 22-24, and 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 (and the similar language recited in 15), the recitation of the element: "a phosphotriesterase-like lactonase having at least 90% identity to the wild-type putative parathion hydrolase from M. tuberclorosis (PPH: SEQ ID NO: 1)" renders the claim indefinite because it is unclear whether the limitations found in the parenthesis are part of the claimed invention. Specifically, here the recitation of “SEQ ID NO: 1” in parenthesis renders the subject matter of the claim indefinite. It is presumed that the claimed enzyme is meant to have at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1, but this is not adequately set forth in the claim.
Further, there is insufficient antecedent basis for the limitation “the wild-type putative parathion hydrolase from M. tuberclorosis” in the claim. Because it is unclear exactly how many putative parathion hydrolases are found in M. tuberculosis, the use of “the” is inappropriate.
As a suggestion to overcome this indefiniteness, the following amendment to the claim is suggested: “a phosphotriesterase-like lactonase having at least 90% identity to a wild-type putative parathion hydrolase from M. tuberculosis (PPH), said wild-type putative parathion hydrolase comprising the amino acid sequence of SEQ ID NO: 1”.
Claim 15 has been determined to be indefinite for the same reasons described for claim 1.
Claim 7 recites the phrase “said phosphotriesterase-like lactonase has an increased thermostability in comparison with thermostability of a non-mutated wild-type phosphotriesterase-like lactonase or substantially similar or higher lactonase catalytic activity provided with N-(3-oxo-hexanoyl)-homoserine lactone as a substrate in comparison with said non-mutated phosphotriesterase-like lactonase.” This phrase renders claim 7 indefinite because there is no previous requirement or recitation of a mutated phosphotriesterase-like lactonase in claim 1, to which this claim depends. Thus, the comparison of thermostability or enzymatic activity with a non-mutated wild-type phosphotriesterase-like lactonase cannot be accomplished, because the claims fully encompass the non-mutated wild-type phosphotriesterase-like lactonase.
Further, the term “substantially similar or higher” in claim 7 is a relative term which renders the claim indefinite. The term “substantially similar or higher” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There would be no way to determine the subject matter encompassed by claim 7, because of the lack of a suitable reference point and the ambiguity of “substantially similar”.
Similarly, claim 8 recites the “method of claim 7, wherein said increased thermostability expressed as T50 is about 50°C to about 80°C; and/or said mutated phosphotriesterase-like lactonase has an extended shelf-life as compared with said non-mutated phosphotriesterase-like lactonase.”. Claim 8 is also indefinite because there is no previous recitation of a mutated phosphotriesterase-like lactonase and thus the comparison to the said non-mutated phosphotriesterase-like lactonase is not possible. Claims 7 and 8 appear to require that the PPH has been mutated, which is a requirement of claim 15 but not of claim 1. Correction is required.
Claim 15 recites “wherein said mutated phosphotriesterase-like lactonase has ... or substantially similar or higher lactonase catalytic activity provided with N-(3-oxo-hexanoyl)-homoserine lactone as a substrate in comparison with said wild-type PPH.”
As described for claim 7 above, the term “substantially similar or higher” in claim 15 is a relative term which renders the claim indefinite. The term “substantially similar or higher” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. How is one to determine if a given mutant enzyme fulfills this condition? There would be no way to determine the subject matter encompassed by claim 7, because of the ambiguity of “substantially similar”.
Claim 15 also recites the phrase: “or in a non-plant food product”, which includes elements that are not actually disclosed thereby rendering the scope of the claim unascertainable. See MPEP § 2173.05(d). In this case, the language use renders the scope of the claim indefinite because there is no special definition provided in the specification for “non-plant food product”. To what extent is one to consider an article a food product? A food product suitable for livestock or pet food may not be considered suitable for human consumption. The specification provides only one example: “in further embodiments, the non-plant food product treated with Method B is shellfish” (see [0069]). From the disclosure there is no way to determine the metes and bounds of a “non-plant food product” which falls within the claimed treatment method’s scope.
All other claims depend directly or indirectly from the rejected claims and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Efremenko et al. (RU-2634914-C2, corresponding to application RU2016148169) in view of Chen et al. ("Quorum quenching enzymes and their application in degrading signal molecules to block quorum sensing-dependent infection." International journal of molecular sciences 14.9 (2013): 17477-17500) and Afriat et al. (“The latent promiscuity of newly identified microbial lactonases is linked to a recently diverged phosphotriesterase.” Biochemistry vol. 45,46 (2006): 13677-86. doi:10.1021/bi061268r), with supporting evidence from UniProt Entry A0A045JWN9 (Parathion hydrolase from Mycobacterium tuberculosis).
Efremenko pertains to a method of using an organophosphate hydrolase exhibiting high lactonase activity with a broad spectrum of action, administered as a highly purified soluble or rehydrated lyophilized preparation, to neutralize not one but several different mycotoxins having a lactone ring, including the mycotoxins patulin (Abstract).
Efremenko teaches the process is for the removal of dangerous mycotoxins, products of fungi metabolism affecting and polluting agricultural raw materials (which encompasses plants), food, and animal feed, both in the process of growing crops and during storage of their processed products, namely, the invention relates to a method for enzymatic hydrolysis of mycotoxins, whose molecules contain a lactone ring, which includes patulin (pg. 2 of the translation).
Efremenko also teaches that “there is great interest in enzymes capable of transforming precisely this lactone ring in the structure of mycotoxins to obtain transformation products that do not have toxicity of the starting material. Among these enzymes that catalyze the hydrolysis of the ether bond in the lactone ring are lactonases.” (pg. 3, 2nd ¶ of the translation).
Efremenko thus teaches using lactonases to perform biological neutralization of mycotoxins having a lactone ring in their structure in complex chemical composition media (pg. 4). Efremenko demonstrates, in Example 4, the successful hydrolysis of patulin in a composition of grain feed under the action of a His-tagged-OPH (organophosphate hydrolase) (pg. 6).
However, Efremenko does not expressly teach that the lactonase administered for patulin degradation to treat a fungal infection in a plant or plant product comprises "a phosphotriesterase-like lactonase having at least 90% identity to the wild-type putative parathion hydrolase from M. tuberclorosis (PPH: SEQ ID NO: 1)", as required of the instant claim 1.
Chen discloses the use of lactonases, quorum quenching enzymes, for the treatment of bacterial infection and teaches means of enzymatic protection in quorum sensing systems for host diseases and their application in resistance against microbial diseases (Title, Abstract). Chen discloses a list of known quorum quenching (QQ) enzymes involved in the degradation of the quorum sensing (QS) signal, including a PPH from Mycobacterium tuberculosis (see Table 1, line 20, which in turn refers to reference 62, Afriat et al.). Chen further teaches that such enzymes have been used as therapeutic tools for controlling plant diseases (see section 7, pgs. 17490-17492). Chen discusses experiments with providing biocontrol enzymes for tomato roots and potato roots, among others (see section 8, pg. 17492).
Afriat et al. teaches a group of microbial lactonases dubbed phosphotriesterase(PTE)-like lactonases (PLLs), and teaches a putative parathion hydrolase (PPH) from Mycobacterium tuberculosis (Figure 1) that has enzymatic activity against various lactones (Table 1, Figure 3). Afriat teaches that these enzymes have conserved TIM-barrel folds (see pg. 13678, left col and pg. 13684, left col, 2nd paragraph: “Structural modeling suggests that the core of the active sites of PLLs and PTE is essentially identical, and the replacement of short loop 7 of PLLs with elongated loop 7 containing a short R-helix seen in PTE may result in “capping” of the active site and narrowing of its “mouth” (Figure 4). In TIM barrels, and in the amidohydrolase superfamily in particular, loops 7 and 8 are most often involved in contacting substrates and in determining substrate specificity (26, 51)”. The sequence of the PPH from M. tuberculosis is displayed in Figure 1 of Afriat. This appears to be identical to that of UniProt Entry A0A045JWN9, which has 98.6% sequence identity to the instantly recited SEQ ID NO: 1 (see APPENDIX A below). The sequences are 100% identical after the first 5 amino acids of the wild-type sequence (indeed the specification confirms that the sequence is lacking the four first N-terminal amino acid residues at [0026]).
Thus, to one having ordinary skill in the art, before the filing date of the instant invention, it would have been obvious in view of the combined teachings of Efremenko, Chen, and Afriat, to modify the methods for protecting plants from fungal infects taught in Efremenko by substituting a phosphotriesterase-like lactonase having at least 90% identity to the wild-type putative parathion hydrolase from M. tuberculosis, particularly, the one taught in Afriat, for the predicted result of providing protection from fungal mycotoxins having lactone structures.
Chen demonstrates a list of known phosphotriesterase-like lactonases, including the PPH from M. tuberculosis identified in Afriat, and teaches that these enzymes are known to have protective effects against pathogens when applied to plants.
Thus, to one of ordinary skill in the art following the methods of Efremenko that include selecting a lactonase and providing the enzyme to agricultural products, including grain feed, for protection against mycotoxins including patulin, it would have been a matter of judicious selection and routine optimization to select from among the promiscuous lactonases known to the art. One having ordinary skill and knowledge of the list of possible phosphotriesterase-like lactonases taught in Chen would have been suitably motivated to substitute any of these analogous enzymes, and, from the teachings of Afriat, one would recognize that the M. tuberculosis PPH has activity against a range of different lactonase-containing compounds. Because of the recognized promiscuity of PPH for lactonases, it is reasonable that it would have degradation activity against the lactone-containing compound patulin.
Therefore, to one of ordinary skill in the art, the substitution of the PPH taught in Chen and Afriat for the organophosphate hydrolase would have predictably resulted in protection from fungal infections involving patulin, because PPH is a promiscuous and highly-active PPL enzyme, according to Afriat. See MPEP § 2143, rationale B, describing the substitution of two similar elements, both known in the art: “it would have been prima facie obvious to substitute one method for the other. Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious." Id. at 301, 213 USPQ at 536.” Further, the teachings of Chen amount to finding that of a finite number of identified, predictable potential enzymes that perform the recognized need to try for protection of plants against patulin, see MPEP § 2143, rationale E, describing that it is “Obvious to try” known potential solutions with a reasonable expectation of success.
Regarding claims 12 and 13, it would have been prima facie obvious to apply the PPH enzyme for degradation against lactone-containing mycotoxins, including patulin, made obvious by the combination of Efremenko, Chen, and Afriat against any potential infection fungus. Further, these limitations only describe parts of the preamble of claim 1, and the practical method steps, that of administering the wild-type PPH from M. tuberculosis to plants would have intrinsically resulted in protection against these fungal infections. Protection against Penicillium expansum and/or related fungi would have naturally followed from the teachings in the art. ("Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent." Bristol-Myers Squibb Co. v. Ben Venue Labs. Inc., 246 F.3d 1368, 1376 (Fed.Cir.2001) (citing In re May, 574 F.2d 1082, 1090 (Cust. & Pat. App.1978)).
Regarding claim 14, Efremenko teaches applying enzymes with lactonase activity to grain feed products, e.g. wheat grain. Regardless, the choice of plant to which to apply the protective enzyme amounts to a matter of judicious selection. One of ordinary skill in the art would recognize that plants susceptible to patulin-producing organisms are the best candidates for the method made obvious by Efremenko, Chen, and Afriat.
From the teachings of the cited references, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because Efremenko teaches successfully using lactonase enzymes for removing patulin from a plant part or plant product and the art (e.g. Chen and Afriat) recognizes that PPH having SEQ ID NO: 1 from M. tuberculosis is a promiscuous, highly active lactonase.
Therefore, the invention of claims 1 and 12-14 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 7-10, 12-18, 22-24, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 18-27 of U.S. Patent No. 12,667,106 in view of Efremenko et al. (RU-2634914-C2, corresponding to application RU2016148169).
Claim 1 of the ‘106 patent recites: “A mutated phosphotriesterase-like lactonase having at least 90% identity with the wild-type putative parathion hydrolase from M. tuberclorosis of SEQ ID NO: 1, in which an amino acid residue corresponding to position 59 or 172 of SEQ ID NO: 1 is substituted, wherein a glycine residue corresponding to G59 is substituted by an amino acid residue selected from valine, alanine, leucine, and isoleucine, or a histidine residue corresponding to H172 is substituted by an amino acid residue selected from tyrosine, phenylalanine and tryptophan, and said mutated phosphotriesterase-like lactonase has substantially identical TIM-barrel fold to a wild-type phosphotriesterase-like lactonase and preserves catalytic residues in its active site.”
Claim 3 of the reference patent recites: “The mutated phosphotriesterase-like lactonase of claim 2 comprising or essentially consisting of the amino acid sequence as set forth in SEQ ID NO: 2”.
Claim 4 recites that the mutated phosphotriesterase-like lactonase has an increased thermostability in comparison with thermostability of a non-mutated wild-type phosphotriesterase-like lactonase or substantially similar or higher lactonase catalytic activity compared to a non-mutated wild-type PLL. Claim 5 states that the enzyme has “increased thermostability expressed as T50 is about 50° C. to about 80° C.”
Claim 18 of the reference patent recites: “A plant or a part, organ or a plant propagation material thereof, at least partly covered or coated with a mutated phosphotriesterase-like lactonase of claim 1.”
Regarding the application of the enzyme to plants, claim 20 of the ‘106 patent recites:
“A method for treating or preventing infection of a bacterium in a plant or a part, organ or a plant propagation material thereof, said plant being infected by or susceptible to a bacterium secreting a lactone selected from N-(3-hydroxybutanoyl)-L-homoserine lactone (C4-HSL), N-(3-oxo-hexanoyl)-homoserine lactone (C6-oxo-HSL), N-[(3S)-tetrahydro-2-oxo-3-furanyl]octanamide (C8-oxo-HSL), and N-[(3S)-tetrahydro-furanyl]decanamide (C10-HSL), said method comprising applying on said plant or said part, organ or plant propagation material thereof, the wild-type putative parathion hydrolase from M. tuberclorosis of SEQ ID NO: 1, the mutated phosphotriesterase-like lactonase of claim 1, or the composition of claim 10.”
Claim 25 of the ‘106 patent recites: “comprising applying the mutated phosphotriesterase-like lactonase wherein a glycine residue corresponding to G59 of SEQ ID NO: 1 is substituted by valine.”
When determining the breadth of the claimed subject matter involving candidate plants to apply the method to, the disclosure of the ‘106 patent includes: “In certain embodiments, the plant is selected from Rosaceae crops, such as apple and pear trees; carrot; potato; tomato; leafy greens; squash and other cucurbits; onion; green peppers; Gesneriacea, such as African violets; beet; and potato.” (Col 15, lines 47-55). MPEP §804.II.B.1. establishes that "The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ " Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004);” and also describes that “the portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.” Further, MPEP §804.II.B.1. also states that “If the reference patent discloses several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to properly construe the reference patent claim and determine whether it anticipates or renders obvious the claim in the application being examined”.
However, the subject matter of the ‘106 patent claims pertains to protection of plants from bacteria pathogens and does not expressly suggest the use of the PPH and mutants thereof for treating fungal diseases involving the degradation of patulin.
The relevant teachings of Efremenko include all of those set forth above. Efremenko discloses a process for the removal of dangerous mycotoxins, products of fungi metabolism affecting agricultural raw materials, food, and animal feed, both in the process of growing crops and during storage of their processed products, namely, the invention relates to a method for enzymatic hydrolysis of mycotoxins, whose molecules contain a lactone ring, which includes patulin (pg. 2 of the translation). Efremenko also teaches that “there is great interest in enzymes capable of transforming precisely this lactone ring in the structure of mycotoxins to obtain transformation products that do not have toxicity of the starting material. Among these enzymes that catalyze the hydrolysis of the ether bond in the lactone ring are lactonases.” (pg. 3, 2nd ¶ of the translation). Efremenko teaches using lactonases to perform biological neutralization of mycotoxins having a lactone ring in their structure in complex chemical composition media (pg. 4). Efremenko demonstrates, in Example 4, the successful hydrolysis of patulin in a composition of grain feed under the action of a His-tagged-OPH (organophosphate hydrolase) (pg. 6).
To one having ordinary skill in the art, the administration of the lactonase enzyme (PPH) of the ‘106 patent, comprising the amino acid sequence of SEQ ID NO: 1 and/or mutants thereof, to plants for treating fungal infections would have been obvious in view of the teachings of Efremenko, demonstrating that analogous lactonase enzymes have activity against patulin.
The application of the wild-type PPH from M. tuberculosis or mutants thereof, including a G59 mutant, to plants is fully encompassed by the subject matter of the ‘106 patent claims. Thus, the performance of the claimed method steps are anticipated if not made obvious by performing the method recited therein. The effects of this lactonase enzyme regarding degradation of patulin would have been predictable over the teachings of Efremenko described above. Thus, the claims 1 and 15 are not patentably distinct over the reference patent claims, in view of the knowledge in the art.
The reference patent claims also disclose that the mutated phosphotriesterase-like lactonase has an increased thermostability in comparison with thermostability of a non-mutated wild-type phosphotriesterase-like lactonase or substantially similar or higher lactonase catalytic activity compared to a non-mutated wild-type PLL, and discloses subject matter in which the enzyme has “increased thermostability expressed as T50 is about 50° C. to about 80° C”, as required of instant claims 7-8, 15, and 22.
For the dependent claims 2-4, 9-10, 16-18, and 23-24 the reference patent claims disclose mutants wherein the glycine residue corresponding to G59 of SEQ ID NO: 1 is substituted by valine, and where the lactonase comprises the amino acid sequence of SEQ ID NO: 2. These properties are all intrinsic to the sequence of the provided PPH enzyme, and thus would have naturally followed from performing the method as made obvious above.
Regarding claims 12 and 13, it would have been prima facie obvious to apply the PPH enzyme for degradation against lactone-containing mycotoxins including patulin as taught in Efremenko. These limitations only describe parts of the preamble of claim 1, and the practical method steps, that of administering the wild-type or a mutated PPH from M. tuberculosis to plants would have resulted in protection against these fungal infections. Protection against Penicillium expansum and/or related fungi would have naturally followed from the teachings in the reference patent and the cited art ("Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent." Bristol-Myers Squibb Co. v. Ben Venue Labs. Inc., 246 F.3d 1368, 1376 (Fed.Cir.2001) (citing In re May, 574 F.2d 1082, 1090 (Cust. & Pat. App.1978)).
In regard to claims 14 and 26, the disclosure of the ‘106 patent indicates that the plant to which the solution is applied encompasses at least apple trees and tomato plants. Efremenko teaches applying enzymes with lactonase activity to grain feed products, e.g. wheat grain. The choice of plant to which to apply the protective enzyme amounts to a matter of judicious selection. One of ordinary skill in the art would recognize that plants susceptible to patulin-producing organisms are the best candidates for the application of PPH and mutants thereof.
Because the instantly claimed methods would have been obvious over the subject matter of the ‘106 patent, in consideration of the teachings of Efremenko, the instant claims are found to be patentably indistinct over the methods in the reference patent claims.
Conclusion
No claims are allowable.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
APPENDIX A: Alignment of A0A045JWN9_MYCTX and SEQ ID NO: 1.
RESULT 2
A0A045JWN9_MYCTX
(NOTE: this sequence has 4 duplicates in the database searched)
ID A0A045JWN9_MYCTX Unreviewed; 326 AA.
AC A0A045JWN9;
DT 09-JUL-2014, integrated into UniProtKB/TrEMBL.
DT 09-JUL-2014, sequence version 1.
DT 18-JUN-2025, entry version 89.
DE SubName: Full=Parathion hydrolase {ECO:0000313|EMBL:CLV49823.1, ECO:0000313|EMBL:VCU48456.1};
DE EC=3.1.8.1 {ECO:0000313|EMBL:CLV49823.1, ECO:0000313|EMBL:VCU48456.1};
OS Mycobacterium tuberculosis.
OC Bacteria; Bacillati; Actinomycetota; Actinomycetes; Mycobacteriales;
OC Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=1773 {ECO:0000313|EMBL:CLV49823.1, ECO:0000313|Proteomes:UP000050139};
Query Match 98.6%; Score 1714; Length 326;
Best Local Similarity 100.0%;
Matches 325; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 6 PELNTARGPIDTADLGVTLMHEHVFIMTTEIAQNYPEAWGDEDKRVAGAIA RLGELKARG 65
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 PELNTARGPIDTADLGVTLMHEHVFIMTTEIAQNYPEAWGDEDKRVAGAIA RLGELKARG 61
Qy 66 VDTIVDLTVIGLGRYIPRIARVAAATELNIVVATGLYTYNDVPFYFHYLGPGAQLDGPEI 125
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 VDTIVDLTVIGLGRYIPRIARVAAATELNIVVATGLYTYNDVPFYFHYLGPGAQLDGPEI 121
Qy 126 MTDMFVRDIEHGIADTGIKAGILKCATDEPGLTPGVERVLRAVAQAHKRTGAPISTHTHA 185
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 MTDMFVRDIEHGIADTGIKAGILKCATDEPGLTPGVERVLRAVAQAHKRTGAPISTHTHA 181
Qy 186 GLRRGLDQQRIFAEEGVDLSRVVIGHCGDSTDVGYLEELIAAGSYLGMDRFGVDVISPFQ 245
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 182 GLRRGLDQQRIFAEEGVDLSRVVIGHCGDSTDVGYLEELIAAGSYLGMDRFGVDVISPFQ 241
Qy 246 DRVNIVARMCERGHADKMVLSHDACCYFDALPEELVPVAMPNWHYLHIHNDVIPALKQHG 305
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 242 DRVNIVARMCERGHADKMVLSHDACCYFDALPEELVPVAMPNWHYLHIHNDVIPALKQHG 301
Qy 306 VTDEQLHTMLVDNPRRIFERQGGYQ 330
|||||||||||||||||||||||||
Db 302 VTDEQLHTMLVDNPRRIFERQGGYQ 326
APPENDIX B: Alignment of SEQ ID NO:1 and SEQ ID NO :1 of US Pat. No. 12,667,106.
RESULT 1
US-17-596-740A-1
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 1, US/17596740A
CURRENT APPLICATION NUMBER: US/17/596,740A
CURRENT FILING DATE: 2022-05-31
PRIOR APPLICATION NUMBER: PCT/IL2020/050673
PRIOR FILING DATE: 2020-06-17
PRIOR APPLICATION NUMBER: 62/862,348
PRIOR FILING DATE: 2019-06-17
NUMBER OF SEQ ID NOS: 115
SEQ ID NO 1
LENGTH: 330
TYPE: PRT
ORGANISM: Mycobacterium tuberculosis
Query Match 100.0%; Score 1738; Length 330;
Best Local Similarity 100.0%;
Matches 330; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MISEFPELNTARGPIDTADLGVTLMHEHVFIMTTEIAQNYPEAWGDEDKRVAGAIA RLGE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MISEFPELNTARGPIDTADLGVTLMHEHVFIMTTEIAQNYPEAWGDEDKRVAGAIA RLGE 60
Qy 61 LKARGVDTIVDLTVIGLGRYIPRIARVAAATELNIVVATGLYTYNDVPFYFHYLGPGAQL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LKARGVDTIVDLTVIGLGRYIPRIARVAAATELNIVVATGLYTYNDVPFYFHYLGPGAQL 120
Qy 121 DGPEIMTDMFVRDIEHGIADTGIKAGILKCATDEPGLTPGVERVLRAVAQAHKRTGAPIS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DGPEIMTDMFVRDIEHGIADTGIKAGILKCATDEPGLTPGVERVLRAVAQAHKRTGAPIS 180
Qy 181 THTHAGLRRGLDQQRIFAEEGVDLSRVVIGHCGDSTDVGYLEELIAAGSYLGMDRFGVDV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 THTHAGLRRGLDQQRIFAEEGVDLSRVVIGHCGDSTDVGYLEELIAAGSYLGMDRFGVDV 240
Qy 241 ISPFQDRVNIVARMCERGHADKMVLSHDACCYFDALPEELVPVAMPNWHYLHIHNDVIPA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ISPFQDRVNIVARMCERGHADKMVLSHDACCYFDALPEELVPVAMPNWHYLHIHNDVIPA 300
Qy 301 LKQHGVTDEQLHTMLVDNPRRIFERQGGYQ 330
||||||||||||||||||||||||||||||
Db 301 LKQHGVTDEQLHTMLVDNPRRIFERQGGYQ 330
Prosecution Insights