DETAILED ACTION
Status of the Claims
Claims 1-2, 5-7, 10, 14, 17, 21, 26, 31, 34-36, 45-46, 51-52, 54, and 56 are currently pending.
Claims 3-4, 8-9, 11-13, 15-16, 18-20, 22-25, 27-30, 32-33, 37-44, 47-50, 53, 55, and 57-59 have been canceled by Applicant.
Claims 1-2, 5-7, 10, 14, 17, 21, 26, 31, 34-36, 45-46, 51-52, 54, and 56 are the subject of this Office Action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 5 is objected to because of the following informalities: Claim 5 recites “wherein the reverse transcriptase polymerizes a cDNA into which the natural NTP is incorporated” in lines 7-8, however, this appears to be a typo since it is normally dNTPs that are incorporated into cDNA. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-2, 5-7, 10, 14, 17, 21, 26, 31, 34-36, 45-46, 51-52, 54, and 56 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 contain 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.
As per MPEP 2163.03(V), while there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
As per 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." Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it").
Finally, MPEP 2163.04 describes the burden on the examiner with regard to the Written Description requirement, stating that in rejecting a claim, the examiner must set forth express findings of fact which support the lack of written description conclusion. These findings should:
(A) Identify the claim limitation(s) at issue; and
(B) Establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed.
In the present case, the disclosure as originally filed lacks sufficient written description support required to show that Applicant was in possession of the full breadth of claimed unnatural nucleotides and reverse transcriptase enzymes.
All claims recite reverse transcription of an RNA moiety with at least one unnatural nucleotide to produce a cDNA moiety with complimentary unnatural nucleotide(s). The specification at multiple locations recites that unnatural nucleotides contain some type of difference in the nucleobase, sugar, and/or phosphate moieties as compared to naturally occurring nucleotides (e.g., as per para [0088], [0104], [0113]-[0114], etc.). However, the disclosure as originally filed only shows an actual reduction to practice for the reverse transcription of RNA moieties with natural nucleotides plus NaM and TPT3 nucleotides to produce cDNA moieties with natural nucleotides plus dNaM and dTPT3 nucleotides, with only naturally occurring (deoxy)ribose sugars and phosphodiester backbones present. Such reduction to practice is clearly shown in the Examples and Figures of the disclosure. Similarly, the claims recite more reverse transcriptases than the three that were reduced to practice in the application, namely, SuperScript® III, SuperScript® IV, and AMV reverse transcriptase.
However, as per MPEP 2163, a showing of an actual reduction to practice is not the only way to show possession. Possession may also be shown by disclosing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention. See MPEP 2163.02. An adequate written description could include any sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention, or by showing that the inventor constructed an embodiment or performed a process that met all the limitations of the claim and determined that the invention would work for its intended purpose. For some arts, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement and information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986) as cited in MPEP 2163.
In the present case, the disclosure acknowledges the lack of knowledge in the art at the time, for example, stating in para [0004] that “while it is clear that different DNA polymerases, T7 RNA polymerase, and E. coli ribosomes are able to productively recognize the [unnatural base pair], the ability of reverse transcriptases, which mediate the only other common DNA/RNA transaction, has not been thoroughly explored, and the only available data suggests that they might not productively recognize the [unnatural base pair]”. This section then recites Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023), which states “the application of [unnatural base pairs] in reverse transcription (rtc), which is a key step for RNA-based SELEX, has not been reported so far.” Note that Eggert only discloses testing commercial reverse transcriptases with the TPT3 and NaM nucleotides.
Therefore, it is reasonable that the specificity of disclosure necessary to satisfy the written description requirement here is much higher than would be needed for other arts for which there is more known and/or are more mature fields of endeavor. In the present case, there is little or nothing present in the disclosure beyond the reduction to practice of TPT3 and NaM using SuperScript® III, SuperScript® IV, and AMV reverse transcriptase. In conclusion, the application lacks sufficient written description support for the full breadth of the claimed invention and therefore the claims are properly rejected.
Claim Rejections - 35 USC § 112(a) – Enablement
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 1-2, 5-7, 10, 14, 17, 21, 26, 31, 34-36, 45-46, 51-52, 54, and 56 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 reverse transcription reactions with TPT3 and NaM using SuperScript® III, SuperScript® IV, and AMV reverse transcriptase, does not reasonably provide enablement for the full breadth of any unnatural nucleotides and any reverse transcriptase (or even for all the claimed reverse transcriptases and unnatural nucleotides comprising the nucleobases depicted in claims 31, 51-52, and/or 54). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). See also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) ("The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation.").
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) and MPEP 2164.01(A)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breath of the claims. While all the above factors have been fully considered and have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, only the most relevant factors are addressed in detail below.
As per MPEP 2164.08, the Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’", citing In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Further, the propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The breath of the claims. All pending claims recite reverse transcription of an RNA moiety with at least one “unnatural nucleotide” to produce a cDNA moiety with complimentary unnatural nucleotide(s). The specification at multiple locations defines unnatural nucleotides as containing some type of difference in the nucleobase, sugar, and/or phosphate moieties as compared to naturally occurring nucleotides (e.g., as per para [0088], [0104], [0113]-[0114], etc.). Therefore, the all claims encompass embodiments wherein the (deoxy)ribose and phosphate moieties are naturally occurring, as well as embodiments wherein they are not naturally occurring. Examples (from the specification) would include methylphosphonate, phosphorothioate, phosphoroamidate and phosphorodithioate internucleotide linkages, as per para [0125], as well as unnatural sugars, such as pentose, deoxypentose, hexose, deoxyhexose, glucose, arabinose, xylose, lyxose, or a sugar "analog" cyclopentyl group, etc., as per para [00118]. Note that even claims 31, 51-52, and 54, which recite the allowed nucleobases, can reasonably encompass unnatural backbone and/or sugar components. Similarly, all claims encompass any reverse transcriptase. Note that while claim 56 limits them to Avian Myeloblastosis Virus (AMV) reverse transcriptase, Moloney Murine Leukemia Virus (MMLV) reverse transcriptase, SuperScript® II (SS II) reverse transcriptase, SuperScript® III (SS III) reverse transcriptase, SuperScript® IV (SS IV) reverse transcriptase, or Volcano 2G (V2G) reverse transcriptase; the specific reverse transcriptase is presented in the alternative (e.g., the reverse transcriptase is either one of the listed, or the reverse transcription reaction takes place in vitro.
The amount of direction or guidance presented and the existence of working examples. The disclosure as originally filed only shows an actual reduction to practice for the reverse transcription of RNA moieties with natural nucleotides plus NaM and TPT3 nucleotides to produce cDNA moieties with natural nucleotides plus dNaM and dTPT3 nucleotides, with only naturally occurring (deoxy)ribose sugars and phosphodiester backbones present, and only with SuperScript® III, SuperScript® IV, and AMV reverse transcriptases.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. As of the effective filing date, the specification states that nucleosides of dNaM, dTPT3, NAM, TPT3, d5SICS and dMMO2bio could be synthesized and triphosphorylated commercially, as per para [0167], although it is noted that only dNaM, dTPT3, NAM, and TPT3 were revealed by the disclosure to be used in RT reactions. Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023), similarly only discloses testing commercially available reverse transcriptases (e.g., AMV, MMLV, SS II, SS IV, and V2G) with the TPT3 and NaM (deoxy)ribonucleotides. Certainly, several other commercially available RTs were known at the time, as well as perhaps a number of cloned RTs that were within reach for the skilled artisan. Additionally, many, many unnatural nucleotides were available for order and/or synthesis, although reasonably only a subset of them could readily be made as triphosphates or phosphoramidites as needed to be incorporated into oligonucleotides as needed to be substrates for RTs.
The level of skill would be high, most likely at the Ph.D. level or equivalent number of years of experience. Persons of ordinary skill in the art are likely able to set up reverse transcription (RT) assays at least with commercially available RTs and commercially available oligos and nucleotides. However, such persons of ordinary skill in this art, given its unpredictability, would have to engage in undue (non-routine) trial and error experimentation to carry out the invention as claimed.
Perhaps the biggest source of unpredictability relevant for the scope of the claims arises from the difficulty or inability to predict which unnatural nucleotides could be used in reverse transcription reactions to successfully make complementary DNAs. As noted herein, by Applicant’s own admission, as stated in para [0004] of the specification as filed, “while it is clear that different DNA polymerases, T7 RNA polymerase, and E. coli ribosomes are able to productively recognize the [unnatural base pair], the ability of reverse transcriptases, which mediate the only other common DNA/RNA transaction, has not been thoroughly explored, and the only available data suggests that they might not productively recognize the [unnatural base pair]”. This section then recites Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023), which states “the application of [unnatural base pairs] in reverse transcription (rtc), which is a key step for RNA-based SELEX, has not been reported so far.” Note that Eggert only discloses testing commercial reverse transcriptases with the TPT3 and NaM nucleotides.
Therefore, it can be concluded that the level of unpredictability in the art for RT reactions using unnatural nucleotides would be extremely high.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification.
Based on the sheer breadth of the claims, especially regarding the RTs and unnatural nucleotides, it is deemed that vast research of an unpredictable nature would be necessary to make or use the invention as claimed. Thus, due to the inadequacies of the instant disclosure, undue experimentation would be required of one of skill in the art to practice the full scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
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 2 and 56 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 pre-AIA the applicant regards as the invention.
Claims 2 and 56 each contains the trademark/trade names SuperScript®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe commercially available reverse transcriptase enzymes and, accordingly, the identification/description is indefinite.
Given that a trademark or trade name is used to identify a source of goods, and not the goods themselves, it is suggested that Applicant amend the claims to properly define the reverse transcriptase enzymes (e.g. using generic descriptions).
As per MPEP 2173: It is of utmost importance that patents issue with definite claims that clearly and precisely inform persons skilled in the art of the boundaries of protected subject matter. Therefore, claims that do not meet this standard must be rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph as indefinite. Further, as per MPEP 2173.02: If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. As currently written, the metes and bounds of the rejected claims are unascertainable for the reasons set forth above, thus the above claim(s) and all dependent claims are rejected under 35 USC 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Claim Rejections – 35 U.S.C. 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 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.
Eggert et al.
Claims 1, 2, 5, 10, 31, and 56 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023).
Regarding claim 1, Eggert discloses a method of reverse transcribing a polynucleotide comprising an unnatural ribonucleotide, comprising reverse transcribing the polynucleotide with a reverse transcriptase in the presence of an unnatural dNTP comprising an unnatural nucleobase, wherein the reverse transcriptase polymerizes a cDNA into which the unnatural dNTP is incorporated as an unnatural nucleotide (e.g., as per Fig. 1 with results in Fig. 3).
Regarding claim 2, Eggert discloses the above method, wherein the polynucleotide is an RNA, optionally wherein the RNA is an mRNA or tRNA (e.g., as per Fig. 1 with results in Fig. 3).
Regarding claim 5, Eggert discloses a method of measuring incorporation of an unnatural nucleotide, comprising
a. transcribing a polynucleotide comprising an unnatural deoxyribonucleotide with an RNA polymerase in the presence of an unnatural NTP comprising a first unnatural nucleobase to produce an RNA comprising a first unnatural nucleotide (“an 80 nt long RNA oligonucleotide containing either rTPT3 or rNaM was prepared by in vitro transcription with T7 RNA polymerase” as per the first full paragraph on p. 1643);
b. reverse transcribing the RNA with a reverse transcriptase in the presence of an unnatural dNTP comprising a second unnatural nucleobase, wherein the reverse transcriptase polymerizes a cDNA into which the unnatural NTP is incorporated as a second unnatural nucleotide (“Apparently, the incorporation of dTPT3 TP opposite rNaM as a template in RNA is generally more efficiently performed by the RTs tested and, to some extent, cDNA synthesis to form a dTPT3:rNaM base pair occurs” as per the right column of p. 1644); and
c. measuring the amount of the second unnatural nucleotide in the cDNA (e.g., as per Fig. 3 and Fig. S11-S29).
Regarding claim 10, Eggert discloses the above method, wherein the amount of the second unnatural nucleotide in the cDNA molecule is measured relative to the amount of the unnatural deoxyribonucleotide in the polynucleotide before transcription (e.g., qualitatively as per Fig. 3 and S11-S29).
Regarding claim 31, Eggert discloses the above method of claim 1, wherein the unnatural ribonucleotide is X, wherein X comprises NaM as the nucleobase of the unnatural ribonucleotide (NaM); and/or wherein the unnatural ribonucleotide is Y, wherein Y comprise TPT3 as the nucleobase of the unnatural ribonucleotide (TPT3) (e.g., NaM and TPT3 were used as per Fig. 1).
Regarding claim 56, Eggert discloses the above method, wherein the reverse transcribing takes place in vitro (e.g., as per pp. 11-12 of the supplementary material).
Leal et al.
Claims 1-2, 5, 10, 17, and 56 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Leal et al. (ACS Synth. Biol., 2015, 4:407−413).
Regarding claim 1, Leal discloses a method of reverse transcribing a polynucleotide comprising an unnatural ribonucleotide, comprising reverse transcribing the polynucleotide with a reverse transcriptase in the presence of an unnatural dNTP comprising an unnatural nucleobase, wherein the reverse transcriptase polymerizes a cDNA into which the unnatural dNTP is incorporated as an unnatural nucleotide (e.g., as per Fig. 4 and “Nevertheless, in both cases, the presence of the AEGIS complement produces full product with considerably less pausing, suggesting that the reverse transcriptase is able to synthesize duplexes containing both the Z·P and P·Z nucleobase pairs” as per p. 409).
Regarding claim 2, Leal discloses the above method, wherein the polynucleotide is present at a concentration less than or equal to about 500 nM (e.g., 0.050 µM RNA template as per the Reverse Transcription in the Absence and Presence of dATP, dPTP, or dZTP section on p. 412).
Regarding claim 5, Leal discloses a method of measuring incorporation of an unnatural nucleotide, comprising:
a. transcribing a polynucleotide comprising an unnatural deoxyribonucleotide with an RNA polymerase in the presence of an unnatural NTP comprising a first unnatural nucleobase to produce an RNA comprising a first unnatural nucleotide;
b. reverse transcribing the RNA with a reverse transcriptase in the presence of an unnatural dNTP comprising a second unnatural nucleobase, wherein the reverse transcriptase polymerizes a cDNA into which the unnatural NTP is incorporated as a second unnatural nucleotide; and
c. measuring the amount of the second unnatural nucleotide in the cDNA (e.g., as per Fig. 4).
Regarding claim 10, Leal discloses the above method, wherein the amount of the second unnatural nucleotide in the cDNA molecule is measured relative to the amount of the unnatural deoxyribonucleotide in the polynucleotide before transcription (e.g., as per Fig. 4).
Regarding claim 17, Leal discloses the above method of claim 1, wherein the RNA or polynucleotide is present during reverse transcription at a concentration less than or equal to about 1 µM (e.g., 0.050 µM RNA template as per the Reverse Transcription in the Absence and Presence of dATP, dPTP, or dZTP section on p. 412).
Regarding claim 56, Leal discloses the above method, wherein the unnatural dNTP is not dTPT3TP; and/or wherein the reverse transcribing takes place in vitro (e.g., as per the Reverse Transcription in the Absence and Presence of dATP, dPTP, or dZTP section on p. 412).
Claim Rejections – 35 U.S.C. 103(a)
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 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.
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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Eggert et al.
Claims 1, 2, 5, 10, 17, 31, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023).
Eggert is relied on as above.
Regarding claim 17, Eggert discloses the above method of claim 1, wherein the RNA or polynucleotide is present during reverse transcription at a concentration of about 1.2 µM (e.g., 12 pmol transcribed RNA in 10 µL reaction as per pp. 11-12 of the supplementary material). Regarding the limitation of the claim that the concentration be less than or equal to about 1 µM, it is noted that as per MPEP § 2144.05, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Note that any allegations of unexpected results and/or criticality of concentrations should be commensurate in scope with the claims to be persuasive.
Spetzler et al. and Eggert et al.
Claims 1, 2, 5, 10, 17, 31, 34-36, 45-46, 51-52, 54, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Spetzler et al. (U.S. PGPub 2016/0069889 A1, cited in IDS of 08/22/2023) in view of Eggert et al. (ChemBioChem, 2019, 20:1642-1645, cited in IDS of 08/22/2023).
Eggert is relied on as above for anticipating and/or rendering obvious claims 1, 2, 5, 10, 17, 31, and 56.
Regarding claim 34, Spetzler discloses a method of screening RNA aptamer candidates comprising:
a. incubating a plurality of different RNA oligonucleotides with a target (e.g., as per para [0041]-[0042]);
b. performing at least one round of selection for RNA oligonucleotides of the plurality that bind to the target (e.g., as per para [0041]-[0042]);
c. isolating enriched RNA oligonucleotides that bind to the target, wherein the isolated enriched RNA oligonucleotides comprise RNA aptamers (e.g., as per para [0041]-[0042]); and
d. reverse transcribing one or more of the RNA aptamers into cDNAs, thereby providing a library of cDNA molecules corresponding to the RNA aptamers (e.g., as per para [0041]-[0042]).
However, it is noted that Spetzler is silent on the limitations of wherein the RNA oligonucleotides comprise at least one unnatural nucleotide, and wherein the cDNAs comprise an unnatural deoxyribonucleotide at the position complementary to the at least one unnatural nucleotide in the RNA aptamer, as set forth in claim 34.
Eggert discloses interconversion between RNA and DNA (i.e., transcription and reverse transcription) using unnatural nucleotides (e.g., TPT3 and NaM as per Fig. 1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to incorporate TPT3 and NaM unnatural nucleotides as per Eggert in the aptamer selection of Spetzler. One of ordinary skill in the art would have been motivated to do so since Spetzler explicitly states that “[t]he random sequence portion of the oligonucleotide can be of any length and can comprise ribonucleotides and/or deoxyribonucleotides and can include modified or non-natural nucleotides or nucleotide analogs” as per para [0039], noting that Spetzler also states that “[t]he SELEX method thus encompasses the identification of high-affinity nucleic acid ligands containing modified nucleotides conferring improved characteristics on the ligand, such as improved in vivo stability or improved delivery characteristics” as per para [0050]. Also note that Eggert explicitly states that their unnatural nucleotides can be beneficial in the selection of aptamers (e.g., as per the introduction section on p. 1642).
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since both references explicitly suggest such incorporation of unnatural nucleotides into selection of aptamers.
Regarding claim 35, Spetzler discloses the above method, wherein the plurality of different RNA oligonucleotides comprises a randomized nucleotide region (e.g., as per para [0039]).
Regarding claim 36, Spetzler discloses the above method, wherein the randomized nucleotide region comprises the at least one unnatural nucleotide (e.g., as per para [0039]).
Regarding claim 45, Spetzler discloses the above method, further comprising analyzing the RNA aptamers for their ability to bind the target (e.g., as per para [0042]).
Regarding claim 46, Spetzler discloses the above method, wherein analyzing the RNA aptamers for their ability to bind the target comprises determining a Kd, kon, or koff; (e.g., as per para [0042]).
Regarding claims 51-52 and 54, Eggert discloses the above method, wherein the at least one unnatural nucleotide comprises NaM and/or TPT3 (e.g., as per Fig. 1).
Conclusion
No claims are allowed.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684