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 .
Claims 1-17 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse the invention of Group II, claims 1-14, drawn to a DNA polymerase, in the paper of 7/22/2026, is acknowledged. Applicant's election without traverse of the following species:
Species Group 1: 1) Alanine at position 411,
Species Group 2: F152E,
Species Group 3: Alanine at position 141 (D141A),
Species Group 4: 1) Glycine at position 412 or functionally equivalent position;
Species Group 5: 1) Proline at position 413 or functionally equivalent position;
Species Group 6: D141A, E143A, L411A, Y412G, F152E;
are acknowledged.
Claims 5, 7, 9, 10, 15-17 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
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 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Applicants filing of an information disclosure statement on 10/4/2024, is acknowledged. Those references considered have been indicated as such.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms: Triton (paragraph [0294]) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are 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 commercial marks.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-4, 6, 8, 11-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 1-4, 6, 8, 11-14 are directed to all possible polymerases comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A. The specification, however, only provides the representative species of that polymerase comprising the amino acid sequence of SEQ ID NO: 1, comprising an alanine or serine at amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these variant DNA polymerases by identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 1-4, 6, 8, 11-14 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that polymerase comprising the amino acid sequence of SEQ ID NO: 1, comprising an alanine or serine at amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A,, does not reasonably provide enablement for any possible polymerase comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and 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).
Claim(s) 1-4, 6, 8, 11-14 are so broad as to encompass any possible polymerase comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A. The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of DNA polymerase mutants and variants broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the variant DNA polymerases required for the claims. Since the amino acid sequence of a protein 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, 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 proteins' structure relates to its function. However, in this case the disclosure is limited to that polymerase comprising the amino acid sequence of SEQ ID NO: 1, comprising an alanine or serine at amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the 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 any possible polymerase comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A, because the specification does not establish: (A) regions of the DNA polymerase enzyme structure which may be modified effecting the nucleic acid synthesis activity and increased rate of incorporation of modified nucleotides; (B) the general tolerance of DNA polymerase enzymes to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of a DNA polymerase enzyme with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required lipase activities and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those DNA polymerase mutants and variants broadly encompassed by the genus.
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 any possible polymerase comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those variant DNA polymerases 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).
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 6, 8, 11-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,512,295. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-19 of U.S. Patent No. 11,512,295 drawn to a polymerase comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 1; comprising the following amino acids: an alanine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; a glycine at amino acid position 412 or an amino acid functionally equivalent to amino acid position 412; and a proline at amino acid position 413 or an amino acid functionally equivalent to amino acid position 413; an alanine or glycine at amino acid position 93 or an amino acid functionally equivalent to amino acid position 93, wherein the polymerase is capable of incorporating a reversible terminator moiety, wherein said polymerase further comprising an amino acid substitution mutation at position 36, 129, 141, 143, 144, 152, 153, 155, 157, 215, 303, 307, 317, 479, 480, 481, 488, 517, 593, 605, or 642 of SEQ ID NO: 1 anticipate/make obvious instant claims 1-4, 6, 8, 11-14 drawn to a polymerase comprising an amino acid sequence that is at least 80% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, wherein the polymerase comprises: an alanine or serine at amino acid position 411 or an amino acid functionally equivalent to amino acid position 411; and an amino acid substitution, wherein said amino acid substitution comprises: P36A, P36H, V93Q, F152E, G155T, D215A, D317A, or K480A.
Closest prior art
Smith et al. (US Patent NO. 8,852,910) teach a number of substitution mutations at each of the three positions of the motif A domain, including positions 411, 412 and 413. Smith et al. teach the family B DNA polymerases isolated from the hyperthermophilic archaeon Thermococcus litoralis having an alanine at position 411, a glycine at position 412 and a isoleucine at position 413. It is acknowledged that Smith et al. does not teach the amino acid sequence of the family B DNA polymerases isolated from the hyperthermophilic archaeon Thermococcus litoralis, however its amino acid sequence is considered inherent to the family B DNA polymerases from Thermococcus litoralis.
In addition to the above taught substitution mutations, Smith et al. teach in addition it is also desirable for the third position (413) be proline when the first two amino acid positions (411 and 412) are substituted.
Smith et al. further teach the above modified DNA polymerases having a substitution mutation at position 411, 412 and 413 with additional substitution mutation positions, including position 141 substituted with an alanine.
Golynskly et al. (US 2020/0131484) teach a number of altered Family B DNA polymerase enzymes for improved incorporation of nucleotides and nucleotide analogues. Golynskly et al. teach such polymerases as 9oN DNA polymerase of SEQ ID NO:1 comprising a substitution of Phe152 with a non-polar, hydrophobic, or uncharged amino acid, for example Gly.
Remarks
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (571) 272-0956. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
8/16/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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