DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on March 9, 2026 has been entered. The claims pending in this application are claims 1 and 3-20 wherein claims 3, 5-7, 19, and 20 have been withdrawn due to the restriction requirement mailed on August 28, 2025. Claims 1, 4, and 8-18 will be examined.
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.
Written Description
Claims 1, 2, 4, and 8-18 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 claims 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is referred to the interim guidelines on written description published on December 21, 1999 in the Federal Register at Volume 64, Number 244, pp.71427-71440.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly 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.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed”. Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The specification provides adequate written description for SEQ ID NO:1 which is wild type of Pyrococcus Horikoshii DNA polymerase and DNA polymerase mutants of SEQ ID NO:1
comprising a first mutation at amino acid position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 which is leucine, isoleucine, valine, alanine, or glycine wherein the DNA polymerase mutants of SEQ ID NO:1 include SDS 25, SDS42 to SDS50, SDS52 to SDS58, SDS63 to SDS67, SDS70, SDS71, SDS73, SDS75, SDS77, SDS79, SDS80, SDS82 to SDS88, SDS91, SDS92, SDS106, and SDS-107 (see paragraphs [0064], [0105] and [0106], SEQ ID No:1, and Tables 6 and 7 of US 2023/0203578 A1, which is US publication of this instant case). However, the specification fails to adequately describe: (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16. The claimed inventions as a whole are not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which are not conventional in the art as of Applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics (as it relates to the claimed inventions as a whole) such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998).
In this instant case, since, according to the specification, SEQ ID NO:1 is wild type of Pyrococcus Horikoshii DNA polymerase, the polymerase recited in claims 1, 2, 4, 17, and 18 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, the polymerase recited in claim 8 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and any kind of mutation at amino acid position 97 or an amino acid position corresponding to position 97 and/or at amino acid position 13 or an amino acid position corresponding to position 13, and/or at amino acid position 726 or an amino acid position corresponding to position 726; and/or at amino acid position 241 or an amino acid position corresponding to position 241, the polymerase recited in claim 9 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine, the polymerase recited in claim 10 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine, the polymerase recited in claim 11 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine, the polymerase recited in claim in claim 12 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine, the polymerase recited in claim 13 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine, the polymerase recited in claim 14 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, the polymerase recited in claim 15 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine, and the polymerase recited in claim 16 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine. Therefore, claims 1, 4, and 8-18 encompass numerous unknown and unidentified polymerase that miss from the disclosure and it is unclear whether these numerous unknown and unidentified polymerase enzymes still have a polymerase activity and/or 3’-5’ exonuclease activity. For example, since SEQ ID NO:1, which is Pyrococcus Horikoshii DNA polymerase, contains 775 amino acids, an amino acid sequence from the polymerase recited in claim 1 that is 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 means that the differences between the amino acid sequence from the polymerase recited in claim 1 and the amino acid sequence of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 are 50 amino acids. Furthermore, since the polymerase recited in claim 1 can have extra sequences on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the polymerase recited in claim 1 can have more than 500 amino acids and the differences between the amino acids of the polymerase recited in claim 1 and the amino acids of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 is more than 50 amino acids and it is unclear how amino acids on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 affect polymerase activity and/or 3’-5’ exonuclease activity of the polymerase recited in claim 1.
Thus, these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have not been described in the specification. In addition, since the specification and available arts do not show that these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have a polymerase activity and/or have 3’-5’ exonuclease activity, the polymerase activities and/or 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase enzymes recited in claims 1, 2, 4, and 8-18 is unpredictable. Therefore, the general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
With limited disclosure provided by the specification, the skilled artisan cannot envision all unknown and unidentified polymerase recited in claims 1, 4, and 8-18 and therefore
conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method used. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of identifying it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Response to Arguments
In page 9, last paragraph bridging to page 10, second paragraph of applicant’s remarks, applicant argues that “[A]mended claim 1 recites a polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 comprising an alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine at amino acid position 409 or an amino acid position corresponding to 409 and at least one mutation at amino acid position 588 or an amino acid position corresponding to 588 which is leucine, isoleucine, valine, alanine, or glycine. The as- filed specification expressly describes polymerase variants encompassed by amended claim 1 that harbor an alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine at amino acid position 409 (see, e.g., paras. [0102] and [0105] of the as-filed specification) and at least one mutation at amino acid position 588 (see, e.g., paras. [0109] and [0110]). Applicant respectfully submits that the claimed polymerase is adequately described in the as-filed specification (see, e.g., paras. [0100], [0102], [0105], [0109], [0110] of the as-filed specification) and thus, a person of ordinary skill in the art would recognize that the inventor had possession of the claimed invention, as amended”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection. since, according to the specification, SEQ ID NO:1 is wild type of Pyrococcus Horikoshii DNA polymerase, the polymerase recited in claims 1, 2, 4, 17, and 18 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, the polymerase recited in claim 8 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and any kind of mutation at amino acid position 97 or an amino acid position corresponding to position 97 and/or at amino acid position 13 or an amino acid position corresponding to position 13, and/or at amino acid position 726 or an amino acid position corresponding to position 726; and/or at amino acid position 241 or an amino acid position corresponding to position 241, the polymerase recited in claim 9 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine, the polymerase recited in claim 10 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine, the polymerase recited in claim 11 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine, the polymerase recited in claim in claim 12 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine, the polymerase recited in claim 13 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine, the polymerase recited in claim 14 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, the polymerase recited in claim 15 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine, and the polymerase recited in claim 16 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine. Therefore, claims 1, 4, and 8-18 encompass numerous unknown and unidentified polymerase that miss from the disclosure and it is unclear whether these numerous unknown and unidentified polymerase enzymes still have a polymerase activity and/or 3’-5’ exonuclease activity. For example, since SEQ ID NO:1, which is Pyrococcus Horikoshii DNA polymerase, contains 775 amino acids, an amino acid sequence from the polymerase recited in claim 1 that is 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 means that the differences between the amino acid sequence from the polymerase recited in claim 1 and the amino acid sequence of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 are 50 amino acids. Furthermore, since the polymerase recited in claim 1 can have extra sequences on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the polymerase recited in claim 1 can have more than 500 amino acids and the differences between the amino acids of the polymerase recited in claim 1 and the amino acids of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 is more than 50 amino acids and it is unclear how amino acids on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 affect polymerase activity and/or 3’-5’ exonuclease activity of the polymerase recited in claim 1.
Thus, these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have not been described in the specification. In addition, since the specification and available arts do not show that these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have a polymerase activity and/or have 3’-5’ exonuclease activity, the polymerase activities and/or 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase enzymes recited in claims 1, 2, 4, and 8-18 is unpredictable. Therefore, the general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Scope of Enablement
Claims 1, 4, and 8-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for making DNA polymerase mutants of SEQ ID NO:1 named as of SEQ ID NO:1 named as SDS 25, SDS42 to SDS50, SDS52 to SDS58, SDS63 to SDS67, SDS70, SDS71, SDS73, SDS75, SDS77, SDS79, SDS80, SDS82 to SDS88, SDS91, SDS92, SDS106, and SDS-107, does not reasonably provide enablement for making (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16. 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 a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (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 claims.”
The Nature of The Invention
The claims are drawn a polymerase. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Since SEQ ID NO:1 is wild type of Pyrococcus Horikoshii DNA polymerase, claims 1, 4, 17, and 18 encompass any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, claim 8 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and any kind of mutation at amino acid position 97 or an amino acid position corresponding to position 97 and/or at amino acid position 13 or an amino acid position corresponding to position 13, and/or at amino acid position 726 or an amino acid position corresponding to position 726; and/or at amino acid position 241 or an amino acid position corresponding to position 241, claim 9 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine, claim 10 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine, claim 11 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine, claim 12 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine, claim 13 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine, claim 14 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, claim 15 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine, and claim 16 encompasses any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine.
Working Examples
The specification provides 3 working examples (see pages 36-47 of US 2023/0203578 A1, which is US publication of this instant case). However, the specification provides no working example for making (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16.
The Amount of Direction or Guidance Provided and The State of The Prior Art
Although The specification provides 3 working examples (see pages 36-47 of US 2023/0203578 A1, which is US publication of this instant case), the specification provides no working example for making (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16. During the process of the prior art search, the examiner has not found any prior art which is related to make the polymerases recited in claims 1, 4, and 8-18.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether: (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18 can be made; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8 can be made; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9 can be made; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10 can be made ; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11 can be made; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12 can be made; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13 can be made; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14 can be made; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15 can be made; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16 can be made.
Although the specification teaches SEQ ID NO:1 which is wild type of Pyrococcus
Horikoshii DNA polymerase and DNA polymerase mutants of SEQ ID NO:1 comprising a first mutation at amino acid position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 which is leucine, isoleucine, valine, alanine, or glycine wherein the DNA polymerase mutants of SEQ ID NO:1 include SDS 25, SDS42 to SDS50, SDS52 to SDS58, SDS63 to SDS67, SDS70, SDS71, SDS73, SDS75, SDS77, SDS79, SDS80, SDS82 to SDS88, SDS91, SDS92, SDS106, and SDS-107 (see paragraphs [0064], [0105] and [0106], SEQ ID No:1, and Tables 6 and 7 of US 2023/0203578 A1, which is US publication of this instant case), the scopes of claims 1, 4, and 8-18 are much broader than the teachings of the specification because, as mentioned in above written description rejection, the polymerase recited in claims 1, 2, 4, 17, and 18 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, the polymerase recited in claim 8 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and any kind of mutation at amino acid position 97 or an amino acid position corresponding to position 97 and/or at amino acid position 13 or an amino acid position corresponding to position 13, and/or at amino acid position 726 or an amino acid position corresponding to position 726; and/or at amino acid position 241 or an amino acid position corresponding to position 241, the polymerase recited in claim 9 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine, the polymerase recited in claim 10 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine, the polymerase recited in claim 11 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine, the polymerase recited in claim in claim 12 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine, the polymerase recited in claim 13 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine, the polymerase recited in claim 14 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, the polymerase recited in claim 15 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine, and the polymerase recited in claim 16 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine. Therefore, claims 1, 4, and 8-18 encompass numerous unknown and unidentified polymerase that miss from the disclosure and it is unclear whether these numerous unknown and unidentified polymerase enzymes still have a polymerase activity and/or 3’-5’ exonuclease activity. For example, since SEQ ID NO:1, which is Pyrococcus Horikoshii DNA polymerase, contains 775 amino acids, an amino acid sequence from the polymerase recited in claim 1 that is 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 means that the differences between the amino acid sequence from the polymerase recited in claim 1 and the amino acid sequence of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 are 50 amino acids. Furthermore, since the polymerase recited in claim 1 can have extra sequences on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the polymerase recited in claim 1 can have more than 500 amino acids and the differences between the amino acids of the polymerase recited in claim 1 and the amino acids of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 is more than 50 amino acids and it is unclear how amino acids on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 affect polymerase activity and/or 3’-5’ exonuclease activity of the polymerase recited in claim 1.
Thus, these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have not been shown in the specification. Without knowing the information of these unknown and unidentified polymerase in the specification, a skilled artisan does not know how to make these unknown and unidentified polymerase recited in claims 1, 4, and 8-18. Furthermore, although claim 1 limits that the mutation at amino acid position 409 is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, since the specification teaches that “[T]o efficiently incorporate modified nucleotides, the DNA polymerase active site needs to be engineered to accommodate a variety of nucleotide structural variants. DNA polymerases evolved mechanisms to ensure selection of the correct nucleotide in order to maintain the integrity and fidelity of the nucleic acid sequence. One such mechanism is the highly conserved region in family B DNA polymerases active site, which includes the amino acids LYP at positions 408-410 of 9° N polymerases” and “amino acids at positions 408, 409, and 410 in a 9º N polymerase are functionally equivalent to amino acids at positions 409, 410, and 411 in wild type of P. abyssi and P. horikoshii” (see paragraphs [0237] and [0238] of US 2023/0203578 A1, which is US publication of this instant case) and the specification and available arts do not show that these unknown and unidentified polymerase recited in claims 1, 4, and 8-18 have a polymerase activity and/or have 3’-5’ exonuclease activity, the polymerase activities and/or 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase recited in claims 1, 4, and 8-18 are unpredictable. In addition, since it is known that, in family D DNA polymerase (PoID) from Pyrococcus Horikoshii, 3’-5’exonuclease activities for mutants D363A, H365A, N453A, H454A, H500A and H563A cannot be detected (see page 158, abstract, page 161, left column, last paragraph, and Figure 3B from Shen et al., Nucleic Acids Research, 32, 158-168, 2004) and claims 1, 4, and 8-18 do not indicate that amino acid at amino acid position 363 or an amino acid position corresponding to position 363 or amino acid position 365 or an amino acid position corresponding to position 365 or amino acid position 453 or an amino acid position corresponding to position 453 or amino acid position 454 or an amino acid position corresponding to position 454 or amino acid position 500 or an amino acid position corresponding to position 500 or amino acid position 563 or an amino acid position corresponding to position 563 of the polymerase recited in claim 1 does not have an amino acid mutation, if amino acid at amino acid position 363 or an amino acid position corresponding to position 363 or amino acid position 365 or an amino acid position corresponding to position 365 or amino acid position 453 or an amino acid position corresponding to position 453 or amino acid position 454 or an amino acid position corresponding to position 454 or amino acid position 500 or an amino acid position corresponding to position 500 or amino acid position 563 or an amino acid position corresponding to position 563 of each of the polymerases recited in claims 1, 4, and 8-18 is substituted by alanine (A), 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase recited in claims 1, 4, and 8-18 may not be detected and are unpredictable.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussion, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. These undue experimentation at least includes to test whether (1) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine as recited in claims 1, 4, 17, and 18 can be made; (2) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine and any kind of mutation in amino acid position 97 or an amino acid position corresponding to position 97 and/or amino acid position 13 or an amino acid position corresponding to position 13, and/or amino acid position 726 or an amino acid position corresponding to position 726; and/or amino acid position 241 or an amino acid position corresponding to position 241 as recited in claim 8 can be made; (3) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation in amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine as recited in claim 9 can be made; (4) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine as recited in claim 10 can be made ; (5) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine as recited in claim 11 can be made; (6) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine as recited in claim 12 can be made; (7) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine as recited in claim 13 can be made; (8) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or an amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine as recited in claim 14 can be made; (9) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine as recited in claim 15 can be made; and (10) any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine as recited in claim 16 can be made.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Response to Arguments
In page 10, last paragraph bridging to page 11, first paragraph of applicant’s remarks, applicant argues that “[A]mended claim 1 recites a polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 comprising an alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine at amino acid position 409 or an amino acid position corresponding to 409 and at least one mutation at amino acid position 588 or an amino acid position corresponding to 588 which is leucine, isoleucine, valine, alanine, or glycine. Applicant respectfully submits that the as-filed specification provides ample direction for a person of ordinary skill in the art to make and use the claimed polymerase, as amended, see e.g., paras. [0235] - [0258] of the as-filed specification. Additionally, Table 6 provides data from 34 variants of the polymerase recited in amended claim 1 in a strand displacing assay (see variants SDS-25, SDS-42, SDS-43, SDS-44, SDS-45, SDS-46, SDS-47, SDS-48, SDS-49, SDS-50, SDS- 52, SDS-53, SDS-54, SDS-55, SDS-56, SDS-57, SDS-58, SDS-67, SDS-71, SDS-72, SDS-75, SDS-79, SDS-80, SDS-82, SDS-83, SDS-84, SDS-85, SDS-86, SDS-87, SDS-88, SDS-91, SDS- 92, SDS-106, and SDS-107 in Table 6 of the as-filed specification). These variants, encompassed by the polymerase of amended claim 1, harbor an alanine at amino acid position 409 or an amino acid position corresponding to 409 and a leucine or valine at amino acid position 588 or an amino acid position corresponding to 588. In addition to these variants from Table 6, the as-filed specification provides embodiments for polymerase variants harboring glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine at amino acid position 409 or an amino acid position corresponding to 409 (see, e.g., para. [0102] of the as-filed specification) as well as embodiments for polymerase variants harboring isoleucine, alanine, or glycine at amino acid position 588 or an amino acid position corresponding to 588 (see, e.g., para. [0109] of the as-filed specification). As such, Applicant respectfully submits that the specification enables one of ordinary skill in the art to use and make the claimed polymerase as recited in amended claim 1 without undue experimentation”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection. Although the specification teaches SEQ ID NO:1 which is wild type of Pyrococcus Horikoshii DNA polymerase and DNA polymerase mutants of SEQ ID NO:1 comprising a first mutation at amino acid position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 which is leucine, isoleucine, valine, alanine, or glycine wherein the DNA polymerase mutants of SEQ ID NO:1 include SDS 25, SDS42 to SDS50, SDS52 to SDS58, SDS63 to SDS67, SDS70, SDS71, SDS73, SDS75, SDS77, SDS79, SDS80, SDS82 to SDS88, SDS91, SDS92, SDS106, and SDS-107 (see paragraphs [0064], [0105] and [0106], SEQ ID No:1, and Tables 6 and 7 of US 2023/0203578 A1, which is US publication of this instant case), the scopes of claims 1, 4, and 8-18 are much broader than the teachings of the specification because, as mentioned in above written description rejection, the polymerase recited in claims 1, 2, 4, 17, and 18 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine and at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, the polymerase recited in claim 8 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and any kind of mutation at amino acid position 97 or an amino acid position corresponding to position 97 and/or at amino acid position 13 or an amino acid position corresponding to position 13, and/or at amino acid position 726 or an amino acid position corresponding to position 726; and/or at amino acid position 241 or an amino acid position corresponding to position 241, the polymerase recited in claim 9 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 97 or an amino acid position corresponding to position 97 which is cysteine, histidine, lysine, serine, threonine, or methionine, the polymerase recited in claim 10 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 13 or an amino acid position corresponding to position 13 which is arginine or histidine, the polymerase recited in claim 11 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 726 or an amino acid position corresponding to position 726 which is aspartic acid, glutamic acid, asparagine, or glutamine, the polymerase recited in claim in claim 12 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, and a mutation at amino acid position 241 or an amino acid position corresponding to position 241 which is leucine, isoleucine, alanine, valine, or glycine, the polymerase recited in claim 13 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 472 or an amino acid position corresponding to position 472 which is asparagine, aspartic acid, glutamic acid, or glutamine, the polymerase recited in claim 14 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 469 or the amino acid position corresponding to position 469 which is threonine, serine, cysteine, or methionine, the polymerase recited in claim 15 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 520 or the amino acid position corresponding to position 520 which is histidine, lysine, or arginine, and/or a mutation at amino acid position 465 or the amino acid position corresponding to position 465 which is asparagine, aspartic acid, glutamic acid, or glutamine, and/or a mutation at amino acid position 491 or the amino acid position corresponding to position 491 which is glycine, valine, leucine, or isoleucine, and the polymerase recited in claim 16 is read as any kind of polymerase comprising an amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, a first mutation at amino acid position 409 or an amino acid position corresponding to position 409 which is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, at least one mutation at amino acid position 588 or an amino acid position corresponding to position 588 which is leucine, isoleucine, valine, alanine, or glycine, and a mutation at amino acid position 93 or the amino acid position corresponding to position 93 which is glutamine, valine, arginine, or alanine. Therefore, claims 1, 4, and 8-18 encompass numerous unknown and unidentified polymerase that miss from the disclosure and it is unclear whether these numerous unknown and unidentified polymerase enzymes still have a polymerase activity and/or 3’-5’ exonuclease activity. For example, since SEQ ID NO:1, which is Pyrococcus Horikoshii DNA polymerase, contains 775 amino acids, an amino acid sequence from the polymerase recited in claim 1 that is 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 means that the differences between the amino acid sequence from the polymerase recited in claim 1 and the amino acid sequence of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 are 50 amino acids. Furthermore, since the polymerase recited in claim 1 can have extra sequences on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1, the polymerase recited in claim 1 can have more than 500 amino acids and the differences between the amino acids of the polymerase recited in claim 1 and the amino acids of any kind of continuous 500 amino acid sequence of SEQ ID NO: 1 is more than 50 amino acids and it is unclear how amino acids on 5’ end and/ 3’ end of the amino acid sequence that is at least 90% identical to a continuous 500 amino acid sequence within SEQ ID NO: 1 affect polymerase activity and/or 3’-5’ exonuclease activity of the polymerase recited in claim 1.
Thus, these unknown and unidentified polymerase enzymes recited in claims 1, 4, and 8-18 have not been shown in the specification. Without knowing the information of these unknown and unidentified polymerase in the specification, a skilled artisan does not know how to make these unknown and unidentified polymerase recited in claims 1, 4, and 8-18. Furthermore, although claim 1 limits that the mutation at amino acid position 409 is alanine, glutamine, tyrosine, phenylalanine, isoleucine, valine, cysteine, serine, or histidine, since the specification teaches that “[T]o efficiently incorporate modified nucleotides, the DNA polymerase active site needs to be engineered to accommodate a variety of nucleotide structural variants. DNA polymerases evolved mechanisms to ensure selection of the correct nucleotide in order to maintain the integrity and fidelity of the nucleic acid sequence. One such mechanism is the highly conserved region in family B DNA polymerases active site, which includes the amino acids LYP at positions 408-410 of 9° N polymerases” and “amino acids at positions 408, 409, and 410 in a 9º N polymerase are functionally equivalent to amino acids at positions 409, 410, and 411 in wild type of P. abyssi and P. horikoshii” (see paragraphs [0237] and [0238] of US 2023/0203578 A1, which is US publication of this instant case) and the specification and available arts do not show that these unknown and unidentified polymerase recited in claims 1, 4, and 8-18 have a polymerase activity and/or have 3’-5’ exonuclease activity, the polymerase activities and/or 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase recited in claims 1, 4, and 8-18 are unpredictable. In addition, since it is known that, in family D DNA polymerase (PoID) from Pyrococcus Horikoshii, 3’-5’exonuclease activities for mutants D363A, H365A, N453A, H454A, H500A and H563A cannot be detected (see page 158, abstract, page 161, left column, last paragraph, and Figure 3B from Shen et al., Nucleic Acids Research, 32, 158-168, 2004) and claims 1, 4, and 8-18 do not indicate that amino acid at amino acid position 363 or an amino acid position corresponding to position 363 or amino acid position 365 or an amino acid position corresponding to position 365 or amino acid position 453 or an amino acid position corresponding to position 453 or amino acid position 454 or an amino acid position corresponding to position 454 or amino acid position 500 or an amino acid position corresponding to position 500 or amino acid position 563 or an amino acid position corresponding to position 563 of the polymerase recited in claim 1 does not have an amino acid mutation, if amino acid at amino acid position 363 or an amino acid position corresponding to position 363 or amino acid position 365 or an amino acid position corresponding to position 365 or amino acid position 453 or an amino acid position corresponding to position 453 or amino acid position 454 or an amino acid position corresponding to position 454 or amino acid position 500 or an amino acid position corresponding to position 500 or amino acid position 563 or an amino acid position corresponding to position 563 of each of the polymerases recited in claims 1, 4, and 8-18 is substituted by alanine (A), 3’-5’ exonuclease activities of these numerous unknown and unidentified polymerase recited in claims 1, 4, and 8-18 may not be detected and are unpredictable.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
No claim is allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
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/FRANK W LU/Primary Examiner, Art Unit 1683
April 29, 2026
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