DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-5 are pending and under consideration in this Office Action.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a broad and widely varying genus of methods for preparing a complementary deoxyribonucleic acid molecule comprising: (a) fragmenting a ribonucleic molecule to yield a plurality of RNA fragments; (b) removing a 3'-phosphate group, a 2'-phosphate group, and cyclic 2'3' phosphate from one or more of said RNA fragments, thereby generating one or more dephosphorylated fragmented RNAs; (c) adding a poly-A tail to said one or more dephosphorylated fragmented RNAs; (d) adding, to said one or more dephosphorylated fragmented RNAs: i. a primer adapter comprising an oligo-T sequence; ii. an acceptor adapter; andiii. a genus of non-naturally occurring R2 enzymes having at least 95% identity to SEQ ID NO:20 and a processivity of 20 nucleotides or longer wherein said non-naturally occurring R2 enzyme reverse transcribes a sequence from said one or more dephosphorylated fragmented RNAs in a 3' to 5' order, wherein said R2 enzyme jumps to a 3'-end of said acceptor adapter upon reaching the 5' end of said one or more dephosphorylated fragmented RNAs. According to MPEP 2163:
“For each claim drawn to a genus: The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014)…”
According to MPEP 2163.02:
“The courts have described the essential question to be addressed in a description requirement issue in a variety of ways. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)).”
The reference of Chica et al. (Curr Opin Biotechnol. 2005 Aug;16(4):378-84; IDS filed 05/20/2025) teaches that the complexity of the structure/function relationship in enzymes has proven to be the factor limiting the general application of rational enzyme modification and design, where rational enzyme modification and design requires in-depth understanding of structure/function relationships. The reference of Singh et al. (Curr Protein Pept Sci. 2017, 18, 1-11; IDS filed 05/20/2025) reviews protein engineering methods including directed evolution, rational design, semi-rational design, and de-novo design; and states that despite the availability of a growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see entire publication especially Figs.1 and 3, and page 7, left column, lines 8-17). The reference teachings only provide guidance for searching and screening for the genus of non-naturally occurring enzymes.
The specification as originally filed does not disclose a representative number of species encompassed by the claimed genus by actual reduction to practice. The specification as originally filed does not provide a correlation between function and structure to enable one of ordinary skill in the art to predict which amino acid sequences and structures correlate with the non-naturally occurring enzyme having an improved jumping activity, improved single-stranded priming efficiency, and/or improved processivity.
The specification as originally filed discloses a modified reverse transcriptase comprising the amino acid sequence of SEQ ID NO: 2.
Hence, the specification does not provide sufficient written description to inform one of ordinary skill in the art that applicants were in possession at the time the application was filed of the claimed broad and widely varying genus of methods for preparing a complementary deoxyribonucleic acid molecule comprising: (a) fragmenting a ribonucleic molecule to yield a plurality of RNA fragments; (b) removing a 3'-phosphate group, a 2'-phosphate group, and cyclic 2'3' phosphate from one or more of said RNA fragments, thereby generating one or more dephosphorylated fragmented RNAs; (c) adding a poly-A tail to said one or more dephosphorylated fragmented RNAs; (d) adding, to said one or more dephosphorylated fragmented RNAs: i. a primer adapter comprising an oligo-T sequence; ii. an acceptor adapter; andiii. a genus of non-naturally occurring R2 enzymes having at least 95% identity to SEQ ID NO:20 and a processivity of 20 nucleotides or longer wherein said non-naturally occurring R2 enzyme reverse transcribes a sequence from said one or more dephosphorylated fragmented RNAs in a 3' to 5' order, wherein said R2 enzyme jumps to a 3'-end of said acceptor adapter upon reaching the 5' end of said one or more dephosphorylated fragmented RNAs.
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 of this title, 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 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Accession A0A0V0TAN8 (16-MAR-2016; IDS filed 05/20/2025) in view of Jamburuthugoda et al. (Nucleic Acids Res. 2014 Jul;42(13):8405-15.Epub 2014 Jun 23; IDS filed 05/20/2025), US20060281079 (12/14/2006; IDS filed 05/20/2025), Thompson et al. (Mob Genet Elements. 2011 May-Jun; 1(1): 29–37; IDS filed 05/20/2025), US20140363854 (12/11/2014; IDS filed 05/20/2025).
Accession A0A0V0TAN8 teaches an enzyme having reverse transcriptase activity and an amino acid sequence that is 100% identical to SEQ ID NO: 2 (see attached record). The teachings of the reference differ from the claims in that the reference does not teach the claimed method for preparing a complementary deoxyribonucleic acid (cDNA) molecule.
Jamburuthugoda et al. teaches a method for generating a non-naturally occurring enzyme (an enzyme derived by mutations introduced in the R2 reverse transcriptase, thereby indicating that the derived enzyme is non-naturally occurring; abstract) comprising: a. expressing a heterologous sequence encoding said non-naturally occurring enzyme in a host (mutant constructs of the Bombyx mori R2 protein (non-naturally occurring enzyme) were transformed into E.coli cells (expressing a heterologous sequence in a host); page 8406, 2nd column, 2nd paragraph), wherein said non-naturally occurring enzyme comprises: i. a finger domain derived from a non-retroviral transposon or from an R2 retrotransposon (mutant R2 proteins had alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the RT domain of 8. mori R2 element, which comprises a finger domain; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2); ii. a thumb domain derived from an R2 retrotransposon (mutant R2 proteins had alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the RT domain of B. mori R2 element, which comprises a thumb domain; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2); iii. a palm domain derived from an R2 retrotransposon (mutant R2 proteins had alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the RT domain of B. mori R2 element, which comprises a palm domain; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2); and iv. an endonuclease domain derived from an R2 retrotransposon (mutant R2 proteins had alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the endonuclease domain of the 8. mori R2 element; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2); b. purifying said non-naturally occurring enzyme from said host, thereby generating said non-naturally occurring enzyme (mutant constructs of the Bombyx mori R2 protein (non-naturally occurring enzyme) were transformed into E. coli cells (host), and purified; page 8406, 2nd column, 2nd paragraph). Jamburuthugoda et al. further discloses wherein at least one of said finger domain from an R2 retrotransposon, said thumb domain of an R2 retrotransposon, or said endonuclease domain of an R2 retrotransposon is derived from an arthropod (mutant constructs of the Bombyx mori R2 protein were used with alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the RT domain of B. mori (arthropod) R2 element, which comprises a finger, thumb, and endonuclease domain; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2). Jamburuthugoda et al. further discloses wherein at least one of said finger domain from an R2 retrotransposon, said thumb domain of an R2 retrotransposon, or said endonuclease domain of an R2 retrotransposon is derived from silkmoth (mutant constructs of the Bombyx mori R2 protein were used with alanine mutations in region -1 and 0, thereby indicating that the mutant proteins had the RT domain of B. mori (silkmoth) R2 element, which comprises a finger, thumb, and endonuclease domain; abstract; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 2nd and 4th paragraphs; page 8409, 1st column, 1st paragraph; Figure 2). Jamburuthugoda et al. further discloses wherein at least one of said finger domain from an R2 retrotransposon, said thumb domain of an R2 retrotransposon, or said endonuclease domain of an R2 retrotransposon is derived from a vertebrate (R2 elements are prevalent in arthropod lineages as well as in vertebrates, which may also be mutated at conserved motifs; abstract; page 8407, 2nd column, 2nd paragraph; Figure 2) or an echinoderm.
Regarding claim 9 Jamburuthugoda et al. further discloses wherein at least one of said finger domain from an R2 retrotransposon, said thumb domain of an R2 retrotransposon, or said endonuclease domain of an R2 retrotransposon is derived from a flatworm or a hydra (R2 elements are prevalent in arthropod lineages as well as in Hydra magnipapillata, which may also be mutated at conserved motifs; abstract; page 8407, 2nd column, 2nd paragraph; Figure 2). Jamburuthugoda et al. further discloses wherein said host is selected from bacteria (mutant constructs of the Bombyx mori R2 protein were transformed into E. coli cells; page 8406, 2nd column, 2nd paragraph), yeast, algae, cyanobacteria, fungi, a plant cell, or any combination thereof. Jamburuthugoda et al. further discloses wherein said host is E.coli (mutant constructs of the Bombyx mori R2 protein were transformed into E.coli cells; page 8406, 2nd column, 2nd paragraph). Jamburuthugoda et al. further discloses wherein said non-naturally occurring enzyme comprises a mutagenized motif-1 sequence (mutant constructs of the Bombyx mori R2 protein were used with alanine mutations in region -1; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 4th paragraph; page 8409, 1st column, 1st paragraph; Figure 2). Jamburuthugoda et al. further discloses wherein said non-naturally occurring enzyme comprises a mutagenized motif 0 sequence (mutant constructs of the Bombyx mori R2 protein were used with alanine mutations in region 0; page 8406, 2nd column, 2nd paragraph; page 8407, 2nd column, 4th paragraph; page 8409, 1st column, 1st paragraph; Figure 2).
US20060281079 teaches a non-naturally occurring enzyme comprising a fusion-tag molecule (fusion proteins (non-naturally occurring) that include the reverse transcriptase and a carrier protein (fusion-tag molecule); paragraphs [0045], [0046]). US20060281079 discloses a fusion-tag molecule that stabilizes a non-naturally occurring enzyme (fusion proteins (non-naturally occurring) that include the reverse transcriptase and a carrier protein (fusion-tag molecule), which provide a form of reverse transcriptase with greater stability; paragraphs [0045], [0046]).
Thompson et al. discloses a non-naturally occurring enzyme comprising a fusion-tag molecule (Bombyx mori R2 construct (non-naturally occurring enzyme) was tagged with a 6X-His tag; page 35, 1st column, 2nd paragraph, and 2nd column, 2nd paragraph; Figure 2). Thompson et al. discloses a His6 fusion-tag molecule attached to a mutant R2 construct (Bombyx mori R2 construct was tagged with a 6X-His tag; page 35, 1st column, 2nd paragraph, and 2nd column, 2nd paragraph; Figure 2). Thompson et al. discloses a His6 fusion-tag molecule attached to a mutant R2 construct (Bombyx mori R2 construct was tagged with a 6X-His tag; page 35, 1st column, 2nd paragraph, and 2nd column, 2nd paragraph; Figure 2).
US20140363854 discloses a non-naturally occurring enzyme comprising a mutagenized thumb sequence (reverse transcriptase comprising one or more mutations (non-naturally occurring enzyme) within the thumb region; paragraph (0151]). US20140363854 discloses a reverse transcriptase with a mutagenized thumb sequence, wherein said mutagenized thumb sequence has an improved single-stranded priming efficiency (reverse transcriptase comprising one or more mutations within the thumb region, such as F309 mutation, which imparts greater fidelity and lesser ability to incorporate incorrect nucleotides during primer extension, thereby indicating improved single-stranded priming efficiency; paragraphs (0151), (0307), (0353]). US20140363854 discloses a reverse transcriptase with a mutagenized thumb sequence, wherein said mutagenized thumb sequence has an improved processivity (reverse transcriptases comprising one or more mutations within the thumb region are capable of producing more nucleic acid product, e.g. cDNA, and more full length product, compared to the corresponding unmutated reverse transcriptase, which would intrinsically be a result of the mutated RT polymerase consecutively incorporating nucleotides into a nucleic acid template without releasing the nucleic acid template, thereby indicating higher processivity; paragraphs (0052), (0151 )). US20140363854 teaches the following in the claims:
16. A method for making one or more nucleic acid molecules comprising mixing one or more nucleic acid templates with one or more polypeptides having reverse transcriptase activity and incubating the mixture under conditions sufficient to synthesize one or more first nucleic acid molecules complementary to all or at least a portion of the one or more nucleic acid templates.
17. The method of claim 1, wherein the one more nucleic acid templates are RNA.
18. The method of claim 17, wherein the nucleic acid templates are mRNA.
19. The method of claim 16, wherein the synthesized molecule is labeled.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed non-naturally occurring enzyme by further modifying the enzyme of Accession A0A0V0TAN8 to further comprise a palm domain as taught by Jamburuthugoda et al. and US20140363854, fusion-tag molecule as taught by US20060281079 and Thompson et al., and mutagenized thumb sequence as taught by Jamburuthugoda et al.; and using the enzyme in the method of US20140363854. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do this in order to obtain a modified reverse transcriptase enzyme having an improved jumping activity, improved single-stranded priming efficiency, and/or improved processivity that can be used to for preparing a complementary deoxyribonucleic acid (cDNA). It would have been obvious to one of ordinary skill in the art to further using the modified enzyme on a heteregoneous plurality of template nucleic acid molecules comprising a plurality of distinct ribonucleic acid (RNA) molecules as routine optimization and/or as desired. One of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success in view of the reference teachings for making modified enzymes. Hence, the claimed invention as a whole is prima facie obvious.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
# Claims 1-5 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11739307, claims 1-19 of U.S. Patent No. 12221633, claims 1-4 of U.S. Patent No. 12221634. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims and/or the specification of the patents teach the claimed method for preparing a complementary deoxyribonucleic acid molecule comprising: (a) fragmenting a ribonucleic molecule to yield a plurality of RNA fragments; (b) removing a 3'-phosphate group, a 2'-phosphate group, and cyclic 2'3' phosphate from one or more of said RNA fragments, thereby generating one or more dephosphorylated fragmented RNAs; (c) adding a poly-A tail to said one or more dephosphorylated fragmented RNAs; (d) adding, to said one or more dephosphorylated fragmented RNAs:i. a primer adapter comprising an oligo-T sequence;ii. an acceptor adapter; andiii. a non-naturally occurring R2 enzyme having at least 95% identity to SEQ ID NO:20 and a processivity of 20 nucleotides or longer wherein said non-naturally occurring R2 enzyme reverse transcribes a sequence from said one or more dephosphorylated fragmented RNAs in a 3' to 5' order, wherein said R2 enzyme jumps to a 3'-end of said acceptor adapter upon reaching the 5' end of said one or more dephosphorylated fragmented RNAs.. Thus, the teachings anticipate the claimed invention.
Conclusion
No claim is allowed.
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/CHRISTIAN L FRONDA/Primary Examiner, Art Unit 1652
