DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Preliminary Amendment filed on December 5, 2023 has been received and entered.
Restriction Requirement
3. Applicant’s election of Group I (claims 1-17 (SEQ ID NO: 52 among other species)) without traverse, on June 3, 2026, is acknowledged.
Claim Disposition
4. Claims 1-29 are pending. Claims 1-17 are under examination. Claims18-29 are withdrawn from further consideration pursuant to 37 CFR 1.12(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Specification
5. The specification is objected to because of the following informalities:
The specification is objected to because trademarks are disclosed and they are not capitalized. The use of the trademark such as Q-Sepharose Fast Flow, has been noted in this application (see page 103, for example). It should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner, which might adversely affect their validity as trademarks.
The specification is objected to because the organism names are not consistently italicized, see “M. col” at the top of page 102 and “M. columbinum” on page 99.
Appropriate correction of the above is required.
Information Disclosure Statement
6. To date no Information Disclosure Statement has been filed. Applicant is reminded of the duty to disclose.
Claim Objection
7. Claims 1-17 are objected to because of the following informalities:
For clarity and precision of claim language, it is suggested that claim 1 is amended to delete reference to a Table in the specification and recite the pertinent information. For clarity it is suggested that claim 1 is amended to recite a single phrase of “comprising”, consisting or consisting essentially of, instead having them together in one claim. To use these terms effectively, the independent claim starts with open language of comprising and then dependent claims usually recite ‘consisting essentially of’ or ‘consisting of’. The dependent claims hereto are also included.
For clarity the organism name should be spelled out in claim 2 at the first occurrence of the acronym.
For clarity and precision of claim language it is suggested that claim 2 is amended to positively recite the limitations, for instance:”…wherein the isolated ADI is recombinantly expressed [[or expressible]] in [[a bacterial host cell, optionally E. coli]] Escherichia coli, as insoluble and refoldable inclusion bodies”.
For clarity it is suggested that claim 3 is amended to read, “….wherein at least [[about]] 10-100% [[or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%]] of the ADI is recombinantly expressed [[or expressible]] in the [[bacterial host cell]] Escherichia coli, as insoluble and refoldable inclusion bodies”.
For clarity it is suggested that claim 4 is amended to read, “…wherein the isolated ADI has ADI activity under physiological conditions [[,optionally]] of temperature, salinity, and pH”.
For clarity it is suggested that claim 5 is amended to spell out the organism name and delete ‘about’.
For clarity it is suggested that claim 6 is amended to delete “consisting of and consisting essentially of”.
For clarity it is suggested that claim 7 is amended to delete the ‘optionally’ statement in its entirety. In addition, claim 7 is objected for the typographical error of “SEQ I NO:1”, which should be ‘SEQ ID NO:1’.
For clarity it is suggested that claim 13 is amended to read, “…or a[[any]] combination thereof”.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 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.
8. Claims 1-17 are rejected under 35 U.S.C. 112, first paragraph, as containingsubject matter which was not described in the specification in such a way as to enableone skilled in the art to which it pertains, or with which it is most nearly connected, tomake and or use the invention.
The claimed invention is directed to an isolated arginine deiminase (ADI) comprising, consisting of, or consisting essentially of an amino acid sequence that is at least 90, 95..….or 100% identical to……excluding SEQ ID NO:1 (see claim 1 in its entirety). The claimed invention broadly comprises any modification in that structures set forth in the Table and does not safe guard any active sites. The invention is not adequately described because it encompasses a large variable genus of enzyme structures that have not been correlated with function or retention of the native function, and the language in the claim is to exclude the native (SEQ ID NO:1). The claimed invention encompasses a large variable genus of polypeptide structures not adequately described. In addition, dependent claims 6-7, have a large number of residue differences that could all be encompassed in the structure. The art generally discloses that a single amino acid change can be detrimental to structure-function relationship, and the claimed invention encompasses an enormous amount of changes. The claimed invention as set forth in claim 1 encompasses fragments which means amino acid residues can be added, substituted, deleted etc., and the specification discloses that not all of the 20 amino acid residues when substituted produced the activity or produced the desired activity/results, see the below excerpt from page 105:
“Additional lysine codon changes were also included in the studies and found to be of varied importance. M94-M184 mutants were studied which changed each of the identified seven mutants to other amino acids using M34 as the background for these changes. Of the twenty amino acids available for substitution at each of the lysine positions, thirteen are left if you ignore the use of lysine (wild type) the original mutation (varies per site), proline (causes structural changes), cysteine (can form disulfides with other molecules, cysteine which can be used for site specific pegylation if desired, M35, M36 and M39.), bulky hydrophobic residues tryptophan, phenylalanine and tyrosine (Lysine is on the surface of the protein and large hydrophobic side chains are unfavorable on the surface of a protein and could cause aggregation). This leaves 13 other amino acids that can be substituted at each of the seven lysine positions, M94-M184. Each was assessed for insoluble expression of ADI from M. columbinum and a select few from each position were refolded, purified and activity compared to the wild type enzyme.
Seven changes were selected and incorporated into a single mutant, M188. This
mutant did not have proper enzyme activity, so each position was converted back to wild type lysines, represented as M189-M195. No single change resulted in the desired phenotype, so each individual mutation was added to find the minimum necessary for the desired phenotype. The K246E substitution was added due to its ability to increase the activity of the enzyme by ~5%. M196 to M122 show the results of the sequential addition. M214, has the desired phenotype and only requires three mutations in addition to the K246E substitution, i.e., K90V, K287A and K295I. M216 and M218 also have the desired phenotype but have four mutations each, in addition to the K246E substitution, with M218 sharing the same three from M214 and M216 sharing only 2 of the three from M214. While the data presented herein demonstrates a number of active mutant ADI proteins with desirable characteristics, it is likely that additional combinations of mutations will result in the same phenotypes and such combinations may be identified using the methods disclosed herein.”
The claimed invention is also directed to the isolated ADI covalently bonded via a linker to at least one PEG with additional limitations for about 10 PEG molecules and the linker can be a laundry list of compounds such as an amide group, ester group etc. The claimed invention is not commensurate in scope with the disclosure in the specification and applicant has not demonstrated possession of the entire genus encompassed in the claims. The specification fails to provide any additional representative species of the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species which are adequately described are representative of the entire genus. 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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. The claimed invention is also directed to a therapeutic composition with the ADI and a pharmaceutically acceptable carrier, however, there are no indicia in the claims as to what is being treated and who the subject is (for example, cancer patient).
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. The claimed genus of polypeptides could include non-functional proteins or proteins with a different function than the one described. Therefore, the genus of claimed polypeptides encompasses widely variant species. Based on the unlimited variations contemplated one skilled in the art would at best expect a protein that is different or at worst a protein that is not functional. Moreover, Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir.1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
9. Claims 1-17 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.
Claim 1 and the dependent claims hereto are indefinite for the recitation of Table A1.1 and A1.2 because the limitations of the specification cannot be imported into the claim. The language in the claim is incomplete since it is missing the information that is recited in the claim and only found in a Table disclosed in the specification. See also claim 7 with similar language.
Claim 1 is also indefinite for the recitation open language (comprising), closed language (consisting of) and intermediate (consisting essentially of) because each of these phrases garners a different scope and should not be recited in the same claim.
Claims 1 and 2 are ambiguous with the recitation of “expressed or expressible” with respect to the isolated ADI in a bacterial host cell (such as E. coli) because the claims recite what is inventive and the phrase expressed refers to something that has already been explicitly done/performed and is being communicated in words, whereas, the phrase expressible describes a concept or feeling that is capable of happening and is being communicated as possible but not performed. Thus the ordinary skilled worker would not know if applicant got expression of the enzyme in the bacterial host or thinks it could be done (based on the vast amount of mutations encompassed in the claims clarity is needed).
Claim 7 is indefinite for the recitation of substitutions being retained relative to SEQ ID NO:1 because independent claim 1 recites that SEQ ID NO:1 is excluded, thus if excluded the structures why are the structures being compared.
Claims 8-14 are indefinite because they recite additional limitations and independent claim 1 has closed language encompassed in the limitations (consisting of and consisting essentially of).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claim(s) 1 and 8-15 is/are rejected under 35 U.S.C. 102(a)(1) and (a) (2) as being anticipated by Huang et al. (US Patent No. 8,663,967, March 4, 2014).
The claimed invention is directed to an isolated arginine deiminase (ADI) comprising, consisting or consisting essentially of an amino acid sequence that is at least 90% identical to a sequence in Table A1.1/A1.2 excluding SEQ ID NO:1. The broadest reasonable interpretation is a structure that is mutated reads on the claim limitations.
Huang et al. teach an arginine deiminase mutant with partial lysine-deficient and preparation and application thereof. The arginine deiminase mutant of the reference has enzymatic activity of degrading arginine into citruline; compared with the arginine deiminase with the amino acid sequence of SEQ ID NO: 1, the amino acid sequence comprises one or more of K9N, T, K59Q, K66R, A, K93E, A, Q, K111R, A, K119Q, L, M, K121Q, I, K122E, L, K126E, S, R, K178I, E, D, K196I, R, K209G, T, D, K243E, V, R, K249D, Q, K263N, Q, K279Y, T, K293R, H, E, K325V, I, K380T, R, E, and K406E, D, S substitutions. Compared with PEG modified natural derived arginine deiminase, the PEG modified arginine deiminase mutant of the present invention retain better bioactivity; and because the quantity of lysine in arginine deiminase is reduced, the PEG modified products are more uniform and can be applied to clinical treatment of hepatoma, melanoma and the like (see abstract). The structure in Huang et al. meets the at least 90% because the recite less mutations than the instant application and has two the of positions substituted as in the instant application (see abstract and entire document). The reference teaches 1, 8 or 10 PEGs with weights like about 2000 with succinlyl group linker (see paragraph 6). Therefore, the limitations of the claims are met by the reference.
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.
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.
11.Claim(s) 1-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (US Patent No. 8,663,967, March 4, 2014) in view of Wu et al. (10, 463, 721, November 5, 2019) and CN108265068, (Zonhon Biopharm Inst. Inc., July 10, 2018).
Huang et al. teach an arginine deiminase mutant with partial lysine-deficient and preparation and application thereof. The arginine deiminase mutant of the reference has enzymatic activity of degrading arginine into citruline; compared with the arginine deiminase with the amino acid sequence of SEQ ID NO: 1, the amino acid sequence comprises one or more of K9N, T, K59Q, K66R, A, K93E, A, Q, K111R, A, K119Q, L, M, K121Q, I, K122E, L, K126E, S, R, K178I, E, D, K196I, R, K209G, T, D, K243E, V, R, K249D, Q, K263N, Q, K279Y, T, K293R, H, E, K325V, I, K380T, R, E, and K406E, D, S substitutions. Compared with PEG modified natural derived arginine deiminase, the PEG modified arginine deiminase mutant of the present invention retain better bioactivity; and because the quantity of lysine in arginine deiminase is reduced, the PEG modified products are more uniform and can be applied to clinical treatment of hepatoma, melanoma and the like (see abstract). The structure in Huang et al. meets the at least 90% because the recite less mutations than the instant application and has two the of positions substituted as in the instant application (see abstract and entire document). The reference teaches 1, 8 or 10 PEGs with weights like about 2000 with succinlyl group linker (see paragraph 6). The primary reference does not per se teach E. coli, however, the secondary reference teaches expression in E. coli for the engineered ADI (recombinant chimeric ADI). The secondary reference also teaches the structure set forth below with 93% sequence identity with SEQ ID NO:52 that possesses the claimed mutations and characteristics such as activity can be construed as an inherent property (see abstract and entire reference). The secondary reference also teaches purity of the product which meets the limitation of substantially endotoxin free. At paragraph ((25) the secondary reference discloses that, “….the compositions described here are about substantially endotoxin free, including, for example, about 95%...free, preferably about 99% ….free, and more preferably about 99.99%.... free.” The tertiary reference explains that most of the arginine deiminase (ADI) is expressed as inclusion bodies in E. coli fermentation, thus providing merely inactive protein aggregates that require artificial refolding to obtain the corresponding biological functions. To solve for this r ADI E. coli expression strains are provided that meet the requirements of pharmaceutical proteins to achieve high expression of proteins (see col. 1-10 and SEQ ID NO:2). The reference also teaches codon opitimization with arginine deiminase from M. hominis comprising the substitutions of K90T, K108R, K216N, K246E, K295A, and which has 59.85% identity with SEQ ID NO:1 of the instant application which substantially excludes the native structure and recites the same substitutions claimed.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claimed invention as obvious. One of ordinary skill in the art would be motivated to combine the teaching of the references because they are analogous art. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
RESULT 2
US-15-125-833-35
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 35, US/15125833
Patent No. 10463721
GENERAL INFORMATION
APPLICANT: TDW Group
TITLE OF INVENTION: ENGINEERED CHIMERIC PEGYLATED ADI AND METHODS OF USE
FILE REFERENCE: TDWG-002/01WO
CURRENT APPLICATION NUMBER: US/15/125,833
CURRENT FILING DATE: 2016-09-13
PRIOR APPLICATION NUMBER: US 61/954,929
PRIOR FILING DATE: 2014-03-18
NUMBER OF SEQ ID NOS: 59
SEQ ID NO 35
LENGTH: 401
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: C4DS9 recombinant chimeric ADI protein
Query Match 93.9%; Score 1909; Length 401;
Best Local Similarity 93.2%;
Matches 373; Conservative 14; Mismatches 13; Indels 0; Gaps 0;
Qy 1 SKINVYSEIGELKEVLVHTPGDEIRRISPSRLDELLFSAILEPNEAIKEHKGFLKILQDK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 SKINVYSEIGELKEVLVHTPGDEIRRISPSRLDELLFSAILEPNEAIKEHKGFLKILQDK 61
Qy 61 GIKVIQLSDLVAETYTYHATQKEREAFIETWLDEAEPALTKDLRAKVRSYVLSKEGTPVA 120
||||||||||||||| ::|:: |:||||| :|||| | |:||:||||::|:|| :| ||
Db 62 GIKVIQLSDLVAETYKHYASEAEKEAFIEKYLDEATPVLSKDMRAKVKNYILSMQGEPVK 121
Qy 121 MVRTMMAGVSKQELNVESETELVVDPMPNLYFTRDPFASAGNGISLNNMKYVTRKRETIF 180
||||||||||||||||||| ||:|||||||||||||||||||||||||||||||||||||
Db 122 MVRTMMAGVSKQELNVESEVELIVDPMPNLYFTRDPFASAGNGISLNNMKYVTRKRETIF 181
Qy 181 AEFIFATHPDYVTTPHWFDRLDEGNIEGGDVFIYNNDTLVIGVSERTNKEAILTIAKKIV 240
||||||||||| ||||||||||||||||||||||| |||||||||||||||||||||||
Db 182 AEFIFATHPDYKTTPHWFDRLDEGNIEGGDVFIYNKDTLVIGVSERTNKEAILTIAKKIK 241
Qy 241 NNKEAKFKKIVAINVPPMPNLMHLDTWLTMVDKDKFLYSPNMLSVLQVWEIDLSAEIEMV 300
||||||||||||||||||||||||||||||||||||||||||||||:||||||| |||||
Db 242 NNKEAKFKKIVAINVPPMPNLMHLDTWLTMVDKDKFLYSPNMLSVLKVWEIDLSKEIEMV 301
Qy 301 ETNKPLADVLESIIGVKPVLIPIAGKGATQLDIDIETHFDGTNYLTIAPGVVVGYSRNIK 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 302 ETNKPLADVLESIIGVKPVLIPIAGKGATQLDIDIETHFDGTNYLTIAPGVVVGYSRNIK 361
Qy 361 TEAALRAAGVTVLSFEGNQLSLGMGSARCMSMPLVREDVK 400
||||||||||||||||||||||||||||||||||||||||
Db 362 TEAALRAAGVTVLSFEGNQLSLGMGSARCMSMPLVREDVK 401
Conclusion
12. No claims are presently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571) 272-0957. The examiner can normally be reached 9-5pm on Monday to Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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