DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-10 and 12-30 have been cancelled. Claims 31-49 have been newly added.
Applicant’s petition under 37 CFR 1.59(b) submitted 3/6/2024 is acknowledged. This petition has not been decided at this point in time.
Applicant’s request for a corrected filing receipt to correct priority information and referenced the 3/6/2024 petition is acknowledged. This request has not been acted upon at this point in time.
For purposes of this Office action, the examiner is assuming that the instant application is a CON of parent application17/512,116 (now issued as U.S. Patent No. 11,551,786) and the 17/512,116 application is a continuation of PCT/US2020/031084, filed on 1 May 2020 with a priority claim to provisional application 62/841,906, filed on 2 May 2019. None of this is reflected on the current filing receipt dated 12/14/2022.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 11 and 31-33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Constantini et al. (2013, of record).
Appendix A Supplementary data Figure 1 provides the following information:
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Supplementary Figure 1. Amino acid sequence alignment and secondary structure of mTagBFP. FP sequence including the relative location of amino acids with secondary structures. Grey shading specify inward facing residues within a correctly folded 11-β-strand barrel. Underlined residues denote location of cysteine and N-glycosylation consensus sequences.
Alignment of mTagBFP (Qy, from supplemental Figure 1 of Constantini et al.) with instant SEQ ID NO: 1 (Db). Positions recited instant claim 1 are underlined.
Query Match 96.0%; Score 1201; DB 1; Length 233;
Best Local Similarity 97.0%;
Matches 226; Conservative 3; Mismatches 4; Indels 0; Gaps 0;
Qy 2 SEELIKENMHMKLYMEGTVDNHHFKCTSEGEGKPYEGTQTMRIKVVEGGPLPFAFDILAT 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SEELIKENMHMKLYMEGTVDNHHFKCTSEGEGKPYEGTQTMRIKVVEGGPLPFAFDILAT 60
Qy 62 KFLYGSKTFINHTQGIPDFFKQSFPEGFTWERVTTYEDGGVLTATQDTSLQDGCLIYNVK 121
|||||||||:|||||||||||||||||||||||||||||||||||||||||| ||||||
Db 61 SFLYGSKTFIDHTQGIPDFFKQSFPEGFTWERVTTYEDGGVLTATQDTSLQDGSLIYNVK 120
Qy 122 IRGVNFTSNGPVMQKKTLGWEAFTETLYPADGGLEGRNDMALKLVGGSHLIANIKTTYRS 181
||||:|||||||||||||||||||||||||||||||||||||||||||||||| ||||||
Db 121 IRGVDFTSNGPVMQKKTLGWEAFTETLYPADGGLEGRNDMALKLVGGSHLIANAKTTYRS 180
Qy 182 KKPAKNLKMPGVYYVDYRLERIKEANNETYVEQHEVAVARYCDLPSKLGHKLN 234
||||||||||||||||||||||||||:|||||||||||||| |||||||||||
Db 181 KKPAKNLKMPGVYYVDYRLERIKEANDETYVEQHEVAVARYSDLPSKLGHKLN 233
The sequence of Constantini et al. includes the N-terminal methionine that is routinely cleaved in recombinant protein production.
The mTagBFP of Constantini et al. is a blue fluorescent protein variant having a substitution of C for S (S114C) at position 114 relative to instant SEQ ID NO: 1. This protein meets the limitations of instant claims 11 and 31-33.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 44-45 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Constantini et al. (2013, of record) in view of Subramanian et al. (U.S. Patent Application Publication 2019/0271690).
Constantini et al. is applied as above and does not explicitly recite nucleic acids and expression vectors containing them.
Subramanian et al. discloses that it would have been routine to produce blue fluorescent proteins recombinantly using nucleic acids that encode them and expression vectors. See at least abstract and claims.
It would have been obvious to produce the mTagBFP variant of Constantini et al. having a substitution of C for S (S114C) at position 114 relative to instant SEQ ID NO: 1 using nucleic acids encoding it and expression vectors as taught by Subramanian et al. One would have been motivated to do so as this would have been conventional at the time of the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 11, 31-34, 44-45, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 17, and 44-46 of U.S. Patent No. 11,551,786 in view of Constantini et al. (of record) and Subramanian et al. (U.S. Patent Application Publication 2019/0271690).
Constantini et al. and Subramanian et al. are applied as above.
Parent application 17/512,116 issued as U.S. Patent No. 11,551,786. There was a restriction in the parent application (see restriction requirement mailed 2/1/2022) separating three methods. Original claims 11-12 directed to proteins were not part of this restriction. These claims has already been cancelled. There is no prohibition against double patenting whether or not the instant application is a CON or a DIV of the parent application.
Issued claim 1 is directed to a computer-implemented method of training a neural network to improve a characteristic of a protein.
Issued claim 7 is directed to a system for improving a characteristic of a protein.
Issued claim 17 is directed a system for improving a characteristic of a protein.
Issued claims 44-46 depend upon claims 1, 7, and 17, respectively. They are directed to a mutated protein comprising a blue fluorescent protein and the novel stabilizing mutations selection from the group consisting of S28A, Y96F, S114T, V124R, T127L, N173H and combinations thereof.
The issued claims would have put one of ordinary skill in the art at the time of the effective filing date in possession of blue fluorescent protein variants within the scope of the instant claims. See S28, Y96, S114, V124, T127, and N173 variants in instant claim 11. See in particular, the S28A blue fluorescent protein variant of instant claim 34
It would have been obvious to produce the blue fluorescent protein variants recombinantly using nucleic acids encoding them and expression vectors as taught by Subramanian et al. Constantini et al. provides a base sequence to use. One would have been motivated to do so as this would have been conventional at the time of the effective filing date.
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.
Claims 11 and 31-49 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 SEQ ID NOS: 5 and 24-28, does not reasonably provide enablement for all blue fluorescent proteins encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The specification defines a blue fluorescent protein (BFP) variant claim 1 as being different from SEQ ID NO: 1 and fluoresces blue light. See specification page 14, lines 1-8.
Figure 8 discloses that several mutations within the scope of the claims result in significantly reduced blue fluorescence compared to SEQ ID NO: 1.
Figure 9 shows improved fluorescence over wild-type (WT, SEQ ID NO: 1) for S28A (SEQ ID NO: 5); S28A plus S114T (SEQ ID NO: 25); S28A plus S114T plus N173H (SEQ ID NO: 26); S28A plus S114T plus N173 H plus Y96F (SEQ ID NO: 27); S28A plus S114T plus N173H plus T127L (SEQ ID NO: 24); and S28A plus S114T plus N173H plus T127L plus Y96F (SEQ ID NO: 28). See also Figure 3A-B. Note that Figure 3A-B does not identify what amino acids were substituted at the named positions. The Bluebonnet variant has the mutations S28A, S114T, N173H, and T127L (SEQ ID NO: 24).
It is unknown from the specification whether the embodiments of SEQ ID NOS: 2-23 retain blue fluorescence activity as compared to SEQ ID NO: 1.
Claim 11 comprises “one or more mutations.” This is considered to include insertions of one or more amino acids and deletion of one or more amino acids at the recited amino acid positions of SEQ ID NO: 1. (See by comparison claim 31 which specifies substitutions.) In addition, any or all of these positions can be substituted with any amino acid. (See by claim 34 by comparison where particular substitutions are specified.)
The specification discloses that the BFP variants of SEQ ID NOS: 2-28 retain blue fluorescent properties. However, the specification does not disclose or enable BFP variants commensurate in scope to the claims (i.e. all insertions, deletions, and substitutions embraced by the claims as well as combinations thereof) that will result in a BFP variant that retains blue fluorescent properties.
It would constitute undue experimentation to determine all BFP embodiments of the claims that would have the blue fluorescent properties. The examples are limited to particular substitutions and particular combinations of substitutions. There are no examples of amino acid insertions or amino acid deletions and these would have been expected to disrupt the tertiary structure or folding of the protein. Likewise, substitution with amino acids such as proline would have been expected to disrupt the tertiary structure or folding of the protein. Any neural network predictions would need to be verified by actual construction and testing of the BFP variant. Again, it is unknown from the specification whether the embodiments of SEQ ID NOS: 2-23 retain blue fluorescence activity as compared to SEQ ID NO: 1.
The scope of the claims is not enabled.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 40-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 40 is confusing in being directed to a fusion protein as it requires nothing more than the blue fluorescent protein variant of SEQ ID NOS: 2-28. That is, the fusion protein partner is not specified. As written, this claim appears to be of the same scope as claim 36.
Claim 41 is confusing in being directed to a fusion protein as it requires nothing more than the blue fluorescent protein variant of claim 11. That is, the fusion protein partner is not specified. As written, this claim appears to be of the same scope as claim 37.
Claims 42 and 43 are confusing in being directed to a protein fragment. The identity of the larger protein comprising SEQ ID NO: 2-28 and SEQ ID NO: 23 is not specified. The metes and bounds of the claimed “fragment” cannot be determined in the absence of the identity of the larger protein. Clarification is requested.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 48 and 49 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 48 and 49 do not further limit the subject matter of claims 44 and 46, respectively. Claim 48 requires nothing more than claim 44. Claim 49 requires nothing more than claim 49. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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