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 .
Status of the Claims
It is acknowledged that the Applicant amended claims 1-4, 8, 12, 14, 18-21, and 26 in the response filed July 24, 2026.
Claims 1-21 and 26 are currently pending. Claims 20, 21, and 26 were withdrawn as directed to unelected subject matter in the previous action.
Claims 1-19 have herein been examined.
Summary of Response to Applicant’s Arguments
This action is in response to the papers filed July 24, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be persuasive. Detailed responses are documented on pages 8-9, 21-22, and 25-26 of this office action. Any new grounds of rejection presented in this Office Action are necessitated by Applicant’s amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
As a result of amendments to the claims, rejections under 35 U.S.C. 112(b) have been withdrawn. However, said amendments have necessitated new rejections under 35 U.S.C. 112(a) and 112(b), which are set forth below.
As a result of amendments to the claims, rejections under 35 U.S.C. 102(a)(1) have been withdrawn and 35 U.S.C. 101, 35 U.S.C. 103, and double patenting rejections have been modified, as set forth below.
As claim 1 has not been found allowable, Applicant’s request to rejoin the withdrawn claims is denied.
Priority
Applicant’s claim to the benefit of provisional US application 63/411,949 is acknowledged, and the effective filing date of the instant application is considered to be 9/30/22.
Claim Rejections - 35 USC § 112
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 1-19 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.
Claims 1-19 are rejected for the recitation of “a polymerase to amplify…, wherein amplifying the nucleic acid template generates ADP” in claim 1 because it is unclear how the ‘wherein’ clause is intended to limit the claimed composition and/or the polymerase. The claims are directed to a composition, and compositions are analyzed with respect to their structure. However, the clause is limiting the intended use of the composition (i.e. in amplifying nucleic acid templates) and not its structure. In addition, it is unclear how the clause would limit the polymerase specifically, given that ADP is not generally a by-product of polymerase enzymatic activity. If the limitation is intended to require that an ADP-generating element (e.g. a recombinase) is present in the composition, the claims must be amended to reflect that meaning.
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 1-19 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 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. This is a new matter rejection.
Claim 1 recites “the first plurality of amplification primers being orthogonal to the second plurality of amplification primers.” In this case, the specification as originally filed provides for first and second pluralities of amplification primers, including a specific embodiment of P5 and P7 lawn primers (par. 72, 135 of PGPub). The amplification primers “may be specific for a particular target nucleic acid that it is desired to amplify, but in other embodiments these sequences may be ‘universal’ primer sequences which enable amplification of any target nucleic acid… which has been modified to enable amplification with the universal primers” (par. 72). Thus, the original disclosure supports a first and second plurality of amplification primers which are configured to amplify or hybridize to different targets. However, the specification does not support ‘orthogonal’ primers, i.e. primers engineered to be entirely non-interacting with other primers so as to bind only to their precise target sequence.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a composition.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The claims are drawn to a composition comprising naturally occurring enzymes and biomolecules including inorganic polyphosphate, polyphosphate kinase, NTPs, a polymerase, nucleic acid templates, and amplification primers. Claims 2-4 additionally require single-stranded nucleotide binding protein, recombinase, or both. Claim 13 restricts the polyphosphate kinase to one having an amino acid sequence as defined in SEQ ID NO: 1 to 3, or a functional variant or fragment thereof. Claim 19 additionally requires a composition of magnesium ions. The markedly different characteristics analysis has been used to determine if the nature-based products are an exception. The nature-based products have been compared to their natural counterparts.
The claims broadly encompass naturally occurring enzymes and biomolecules and there is no indication that the natural products – inorganic polyphosphate, polyphosphate kinase, NTPs, polymerase, nucleic acid templates, amplification primers, single-stranded nucleotide binding protein, recombinase, or magnesium ions – of the instant claims have any characteristics that are different from the naturally occurring enzymes or biomolecules. There is no difference in function, structure, or other properties from the recited generic enzymes and biomolecules and those found in nature.
Regarding claim 13, SEQ ID NO: 1 represents a sequence which is structurally identical to a naturally occurring polypeptide from Thermus thermophilus, as evidenced by UniProt Database entry: Q72JY1_THET2 (from Henne et al. The genome sequence of the extreme thermophile Thermus thermophilus. Nat. Biotechnol. 22:547-553(2004)). SEQ ID NO: 2 represents a sequence which is structurally identical to a naturally occurring polypeptide from Meiothermus ruber, as evidenced by UniProt Database entry: PK23_MEIRD (from Chin et al. A new subfamily of polyphosphate kinase 2 (class III PPK2) catalyzes both nucleoside monophosphate phosphorylation and nucleoside diphosphate phosphorylation. Appl. Environ. Microbiol. 80:2602-2608(2014)). SEQ ID NO: 3 represents a sequence which is structurally identical to a naturally occurring polypeptide from Escherichia coli, as evidenced by UniProt Database entry A0A0E0XW60_ECO1C (from Ahmed et al. Genomic comparison of Escherichia coli O104:H4 isolates from 2009 and 2011 reveals plasmid, and prophage heterogeneity, including Shiga toxin encoding phage stx2. PLoS ONE 7:E48228-E48228(2012)). There is no difference in function, structure, or other properties from the recited polyphosphate and polyphosphate kinase and those found in nature.
It is noted that the natural products are recited as being in a composition alongside non-natural products such as a solid substrate coupled to pluralities of amplification primers which are orthogonal to one another and hybridize to the nucleic acid template. There is no indication that these elements being present in the composition changes the function, structure, or other properties of the natural products. Claims 18 and 19 are directed toward the composition in the form of a “kit.” The natural products do not interact with other elements of the composition in the “kit.” There is no indication that the natural products being present in a “kit” changes the structure, function, or other properties of the natural products. Because the claimed polyphosphate kinase and polyphosphate do not have markedly different characteristics, they are a product of nature exception.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
In addition to the natural products, the claims recite “a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers” and that the nucleic acid template is “bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers.” These limitations are insufficient to make the claims eligible, as they do not alter the characteristics of the natural products and merely limit the nature-based products to a particular technological environment.
In addition to the natural products, the claims recite intended uses and other functional language. As product claims are analyzed relative to their structure, these limitations do not limit the scope of the claims. These limitations do not practically integrate the judicial exceptions and are the equivalent of adding the words “apply it” to the judicial exceptions.
In addition to the natural products, Claims 15-16 recite the additional element of a buffer. Because some form of reagent is always present in a buffer, this element does not practically integrate the judicial exceptions and is the equivalent of adding the words “apply it” to the judicial exception.
In addition to the natural products, Claims 18 and 19 recite the additional element of a “kit.” A “kit” broadly encompasses a collection of reagents. It fails to meaningfully limit the claims and is the equivalent of adding the words “apply it” to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the natural products, the claims recite “a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers” and that the nucleic acid template is “bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers.” At the time the invention was made, these elements were well-known, routine, and conventional in the art. Thus, the claims as whole do not amount to significantly more than each “product of nature” by itself, and the claims do not qualify as eligible subject matter.
In addition to the natural products, the claims recite intended uses and other functional language. As product claims are analyzed relative to their structure, these limitations do not limit the scope of the claims. Thus, the claims as whole do not amount to significantly more than each “product of nature” by itself, and the claims do not qualify as eligible subject matter.
In addition to the natural products, Claims 15-16 recite the additional element of a buffer and claims 18 and 19 recite the additional element of a “kit.” . At the time the invention was made, buffering enzymes or amplification compositions was well-known, routine, and conventional in the art. At the time the invention was made, kits were well-established, routine, and conventional. Thus, the claims as whole do not amount to significantly more than each “product of nature” by itself, and the claims do not qualify as eligible subject matter.
Response to Arguments
In the response filed July 24, 2026, Applicant stated that the amendments to claim 1 recite an arrangement of elements that is made by man and not found in nature and clarify the inventive function of the polyphosphate and polyphosphate kinase in such an arrangement. Applicant argued that the amended claim is therefore directed to patentable subject matter.
This argument has been considered but is not found to be persuasive. As explicated in the modified rejection above, the inclusion of non-natural elements in the composition and intended use language does not change the characteristics of the natural product and does not provide sufficient integration into a practical application or an inventive concept such that the claims qualify as eligible subject matter. See the modified rejection above for further discussion.
Claim Rejections - 35 USC § 103
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-5, 7, 10, 11, and 15-19 are rejected under 35 U.S.C. 103 as unpatentable over Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), in view of Gunderson (published May 24, 2018; Patent Application Publication US 20180141020) and Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204).
As noted in MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Accordingly, the claim language of “the amplification composition” merely sets forth the intended use of the claimed composition, but does not limit the scope of the claims.
Regarding claim 1, Tavanti teaches compositions comprising inorganic polyphosphate and a polyphosphate kinase (Introduction).
Regarding claim 1, Tavanti does not teach that the composition comprises a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers; or a nucleic acid template bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers.
Regarding claims 1-4, Tavanti does not teach amplification compositions comprising a recombinase, a single-stranded binding protein, and/or a polymerase
Regarding claim 1, Gunderson teaches compositions which comprise a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers; and a nucleic acid template bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers (par. 38, 41, 67, 77; Figure 2).
Regarding claims 1-4, Gunderson teaches amplification compositions comprising a recombinase, a single-stranded binding protein, and a polymerase (par. 184).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Gunderson and Tavanti. One would have been motivated to do so in order to prevent or reduce seeding and amplification from non-target polynucleotides (par. 179). One would have had reasonable expectation of success because Gunderson demonstrates that appropriate solid substrate compositions may be formulated and support nucleic acid amplification (par. 238; Figure 10).
Regarding claim 1, neither Tavanti nor Gunderson explicitly teach the presence of NTPs in the composition.
Piepenburg teaches an amplification composition which comprises a recombinase, a single-stranded binding protein, a polymerase, and NTPs (pg. 1118 – “RPA conditions”).
Regarding claims 15 and 16, Tavanti does not explicitly teach any particular buffer or pH. However, Gunderson teaches the use of buffers in amplification compositions for the purpose of reconstitution (par. 237).
Piepenburg teaches a buffer (pg. 1118 – “RPA conditions”), which buffers the composition at a pH of 7.9. A pH of 7.9 is within claimed range (“about 6.0 to about 9.0”), and therefore Piepenburg’s composition is considered to meet the limitation of the claim.
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Tavanti and Gunderson with the teachings of Piepenburg. One would have been motivated to do so in order to utilize a less expensive and unstable system of ATP-regeneration (Tavanti: pg. 3566, col. 1, par. 1) for a widely accessible nucleic acid-based testing method (Piepenburg: Introduction, par. 1).
Regarding claim 1, the combined references do not explicitly teach that the polyphosphate kinase is present to increase clustering kinetics and increase sequencing signal intensity by recycling ADP to ATP using the inorganic polyphosphate, nor that the polymerase is present to amplify the nucleic acid template using the NTPs and the first plurality of amplification primers. The combined references do not teach that amplifying the nucleic acid template generates ADP. However, compositions are analyzed with respect to their structure. Therefore, these limitations represent intended uses which do not limit the scope of the claims.
Nevertheless, note that Tavanti does teach that recycling ADP to ATP is a quality possessed by polyphosphate kinases (Tavanti: pg. 3566, col. 1, par. 1), Gunderson teaches that polymerases possess the property of amplifying nucleic acid templates using primers (Gunderson: par. 184), and Piepenburg teaches recombinase-based amplification methods where ADP is a byproduct (Piepenburg: pg. 1115, col. 1, last par.).
Regarding claim 5, Tavanti teaches concentrations of inorganic phosphate of 200 and 500 mM (pg. 3576, col. 1, 2nd full par.). The values of 200 mM and 500 mM fall within the range about 0.01 mM to about 1000 mM and therefore the limitation is considered to be met.
Regarding claim 7, Tavanti teaches an inorganic polyphosphate with less than 50 phosphate residues (pg. 3568, col. 1). In addition, pyrophosphate is an inorganic polyphosphate that would be present in the amplification composition as a byproduct of amplification (pyrophosphate has two phosphate groups).
Regarding claims 10 and 12, Tavanti teaches the use of thermophilic polyphosphate kinases and polyphosphate kinases (pg. 3570, col. 2: “ATP Regeneration…”) and polyphosphate kinases from the PPK1 and PPK2 families (pg. 3566, col. 2).
Regarding claim 17, the combined references teach the composition of claim 1. As compositions are analyzed with respect to their structure, the recited intended uses do not limit the scope of the claims. Nevertheless, Gunderson does teach compositions which are clustering compositions (par. 167, 179) or sequencing-by-synthesis compositions (par. 180) or used for resynthesis (i.e. bridge amplification – par. 187).
Regarding claims 18 and 19, Tavanti teaches metal cofactor compositions which comprise magnesium ions (pg. 3568, col. 1, last par.). As the term “kit” broadly encompasses a collection of reagents, the limitation of “kit” is considered to have been met.
Claims 6, 11, and 13 are rejected under 35 U.S.C. 103 as unpatentable over Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), in view of Gunderson (published May 24, 2018; Patent Application Publication US 20180141020) and Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), as applied to claim 1 above, and further in view of Kuroda et al (published Feb 4, 2013; JP 2013021967A) and Motomura et al. (published Apr. 2014; Motomura et al. Appl Environ Microbiol. 2014 Apr;80(8):2602-8).
Tavanti, Gunderson, and Piepenburg teach the limitations of claim 1, as discussed above.
Regarding claim 6, 11, and 13, the combined references do not teach any explicit concentration or optimum working temperature of polyphosphate kinase, nor explicitly that polyphosphate kinase comprises an amino acid sequence as defined in SEQ ID NO: 1 to 3 (or a functional variant or functional fragment thereof).
Kuroda teaches multiple polyphosphate kinases, including one from Meiothermus ruber which corresponds to SEQ ID NO: 2 (par. 83). Note that the sequence in Kuroda is also termed “SEQ ID NO: 2”. Kuroda teaches that the optimum working temperature for this enzyme is 70ºC (par. 91-95; Table 1 on page 83) and using the enzyme at a concentration of 8 ug/mL. Given an approximate molecular mass of 31.6 kDa (Motomura, pg. 2603: “Cloning and purification of class III PPK2”), the enzyme is at a concentration of 0.25 µM in the reaction. Kuroda also teaches a preference of 1 – 500 µg/ml (par. 41; for M. ruber, this would be around 0.03 – 16 µM). Therefore, the limitation that concentration be between 0.01µM – 1000µM is considered to be met.
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Tavanti, Piepenburg, and Gunderson with the teachings of Kuroda. One would have been motivated to do so because a thermophilic PPK2, such as the one from M. ruber, is heat-resistant and can more stably produce ATP from AMP (par. 16).
Claims 8 and 9 are rejected under 35 U.S.C. 103 as unpatentable over the combination of Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), in view of Gunderson (published May 24, 2018; Patent Application Publication US 20180141020) and Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), as applied to claims 1 and 7 above, and further in view of Zhang et al. (published December 16, 2002; Zhang et al. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16678-83).
Tavanti, Gunderson, and Piepenburg teach the limitations of claims 1 and 7, as discussed above.
Regarding claims 8 and 9, the combined references do not explicitly teach that a second inorganic polyphosphate has more than 100 residues, nor any specific ratio of a first inorganic polyphosphate to a second inorganic phosphate. However, although Tavanti does not explicitly teach that a ratio of the first and second inorganic polyphosphates is about 90:10 to 10:90, Tavanti does teach that the relative concentration of substrate inorganic polyphosphate to product can be altered in the course of routine experimentation to achieve results such as a higher final ATP concentration (pg. 3576, col 1). Absent evidence that the ratio of first and second inorganic polyphosphates is critical, it would be obvious to try optimizing the ratio by altering the concentration of the substrate inorganic polyphosphate. One would be motivated to do so, given that the relative concentration is a known results effective variable.
Regarding claim 8, Zhang teaches a polyphosphate kinase (PPK2) which can use inorganic polyphosphate with between 15 and 700 phosphate residues (pg. 16681, col. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Tavanti with the teachings of Zhang. One would have been motivated to do so in order to use a polyphosphate kinase which has a relatively wide substrate specificity (Tavanti, referring to Zhang’s enzyme: pg. 3567, col 1, 1st par.)
Claim 14 is rejected under 35 U.S.C. 103 as unpatentable over Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), in view of Gunderson (published May 24, 2018; Patent Application Publication US 20180141020) and Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), as applied to claim 1 above, and further in view of Ge et al. (published Dec 8, 2011; Ge et al. PLoS One. 2011;6(12): e28707).
Tavanti, Gunderson, and Piepenburg teach the limitations of claim 1, as discussed above.
Regarding claim 14, the combined references do not explicitly teach that the composition does not comprise PEG.
Ge teaches that for the purposes of macromolecular crowding of enzymatic reactions, PEG is an equivalent of polymers such as Ficoll and dextran (pg. 2, col. 1, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to substitute PEG for a different macromolecular crowding agent such as Ficoll or dextran. One would have been motivated to do so because PEG, Ficoll, and dextran were known in the art as macromolecular crowding agents. Furthermore, one may have been motivated to substitute PEG with another crowding agent because it is known to have strong inhibitory effects on processes involving enzymes like polymerases, perhaps due to its ability to cause precipitation (pg. 7, col. 1, 1st par.).
Claims 1-5, 7, 10, 12, and 15-19 are rejected under 35 U.S.C. 103 as unpatentable over the combination of Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7): e204), Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), and Gunderson (published May 24, 2018; Patent Application Publication US 20180141020).
Regarding claims 1-4 and 17, Piepenburg teaches an amplification composition which comprises a recombinase, a single-stranded binding protein, a polymerase, and NTPs (pg. 1118 – “RPA conditions”). While Piepenburg does not explicitly teach that the amplification composition is a clustering composition or a sequencing-by-synthesis amplification composition or a resynthesis composition, these limitations are intended uses of the composition which do not limit the scope of the claims.
Regarding claims 15 and 16, Piepenburg teaches a buffer (pg. 1118 – “RPA conditions”), which buffers the composition at a pH of 7.9. A pH of 7.9 is within the range required by claim 16 (“buffered to a pH of about 6.0 to about 9.0”), and therefore Piepenburg’s composition is considered to meet the limitation of the claim.
Regarding claims 18 and 19, the combination of Piepenburg teaches a metal cofactor composition comprising magnesium ions (pg. 1118 – “RPA conditions”). A “kit” broadly encompasses a collection of reagents; therefore, the limitation of “kit” is considered to have been met.
Regarding claim 1, Piepenburg does not teach inorganic polyphosphate and polyphosphate kinase.
Regarding claims 5 and 7, Piepenburg does not teach any concentration of inorganic polyphosphate or any number of phosphate residues.
Regarding claims 10 and 12, Piepenburg does not teach polyphosphate kinases which are thermophilic or from any specific family.
Regarding claim 1, Tavanti teaches inorganic polyphosphate and polyphosphate kinase (pg. 3566, col 2, par 1).
Regarding claims 5 and 7, Tavanti teaches concentrations of inorganic polyphosphate of 200 mM and 500 mM (pg. 3576, col. 1, 2nd full par.). Here, the concentration of inorganic phosphate was varied during routine experimentation, in order to alter the yield of ATP. The values of 200 mM and 500 mM fall within the range about 0.01 mM to about 1000 mM and therefore the limitation is considered to be met. Tavanti teaches an inorganic polyphosphate with less than 50 phosphate residues (pg. 3568, col. 1).
Regarding claims 10 and 12, Tavanti teaches the use of thermophilic polyphosphate kinases and polyphosphate kinases (pg. 3570, col. 2: “ATP Regeneration…”) and polyphosphate kinases from the PPK1 and PPK2 families (pg. 3566, col. 2).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Piepenburg and Tavanti. One would have been motivated to do so in order to utilize an equivalent but alternative ATP-regeneration system which is less expensive and unstable than creatine kinase + creatine phosphate (Tavanti: pg. 3566, col 1).
Regarding claim 1, Tavanti and Piepenburg do not explicitly teach that the composition comprises a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers; or a nucleic acid template bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers.
Gunderson teaches compositions which comprise a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers; and a nucleic acid template bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers (par. 38, 41, 67, 77; Figure 2).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Gunderson with the teachings of Piepenburg and Tavanti. One would have been motivated to do so in order to prevent or reduce seeding and amplification from non-target polynucleotides (par. 179). One would have had reasonable expectation of success because Gunderson demonstrates that appropriate solid substrate compositions may be formulated and support nucleic acid amplification (par. 238; Figure 10).
Regarding claim 1, the combined references do not teach that the polyphosphate kinase is present to increase clustering kinetics and increase sequencing signal intensity by recycling ADP to ATP using the inorganic polyphosphate, nor that the polymerase is present to amplify the nucleic acid template using the NTPs and the first plurality of amplification primers. The combined references do not teach that amplifying the nucleic acid template generates ADP. However, compositions are analyzed with respect to their structure. Therefore, these limitations represent intended uses which do not limit the scope of the claims.
Nevertheless, note that Tavanti does teach that recycling ADP to ATP is a quality possessed by polyphosphate kinases (Tavanti: pg. 3566, col. 1, par. 1), Gunderson teaches that polymerases possess the property of amplifying nucleic acid templates using primers (Gunderson: par. 184), and Piepenburg teaches recombinase-based amplification methods where ADP is a byproduct (Piepenburg: pg. 1115, col. 1, last par.).
Claims 8 and 9 are rejected under 35 U.S.C. 103 as unpatentable over the combination of Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), and Gunderson (published May 24, 2018; Patent Application Publication US 20180141020), as applied to claims 1 and 7 above, and further in view of Zhang et al. (published December 16, 2002; Zhang et al. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16678-83).
Piepenburg, Tavanti, and Gunderson teach the limitations of claims 1 and 7, as discussed above. Note that this 35 U.S.C. 103 rejection is distinct from the rejection documented on pg. 13-14 of this action because it relies on Piepenburg as a primary reference instead of Tavanti.
Regarding claims 8 and 9, the combined references do not explicitly teach that a second inorganic polyphosphate has more than 100 residues, nor any specific ratio of the first inorganic polyphosphate to the second inorganic phosphate. However, Tavanti teaches that the relative concentration of substrate inorganic polyphosphate to product can be altered in the course of routine experimentation to achieve results such as a higher final ATP concentration (pg. 3576, col 1). Absent evidence that the ratio of first and second inorganic polyphosphates is critical, it would be obvious to try optimizing the ratio by altering the concentration of the substrate inorganic polyphosphate. One would be motivated to do so, given that the relative concentration is a known results effective variable.
Regarding claim 8, Zhang teaches a polyphosphate kinase (PPK2) which can use inorganic polyphosphate with between 15 and 700 phosphate residues (pg. 16681, col. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Piepenburg, Tavanti, and Gunderson with the teachings of Zhang. One would have been motivated to do so in order to use a polyphosphate kinase which has a relatively wide substrate specificity (Tavanti, referring to Zhang’s enzyme: pg. 3567, col 1, 1st par.).
Claims 6, 11, and 13 are rejected under 35 U.S.C. 103 as unpatentable over the combination of Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), and Gunderson (published May 24, 2018; Patent Application Publication US 20180141020), as applied to claim 1 above, and further in view of Kuroda et al (published Feb 4, 2013; JP 2013021967A) and Motomura et al. (published Apr. 2014; Motomura et al. Appl Environ Microbiol. 2014 Apr;80(8):2602-8).
Piepenburg, Tavanti, and Gunderson teach the limitations of claim 1, as discussed above. Note that this 35 U.S.C. 103 rejection is distinct from the rejection documented on pg. 14-15 of this action because it relies on Piepenburg as a primary reference instead of Tavanti.
Regarding claim 6, 11, and 13, the combined references do not explicitly teach any concentration or optimum working temperature of the polyphosphate kinase, nor explicitly that the polyphosphate kinase comprises an amino acid sequence as defined in SEQ ID NO: 1 to 3 (or a functional variant or functional fragment thereof).
Kuroda teaches multiple polyphosphate kinases, including one from Meiothermus ruber which corresponds to SEQ ID NO: 2 (par. 83). Note that the sequence in Kuroda is also termed “SEQ ID NO: 2”. Kuroda teaches that the optimum working temperature for this enzyme is 70ºC (par. 91-95; Table 1 on page 83) and using the enzyme at a concentration of 8 ug/mL. Given an approximate molecular mass of 31.6 kDa (Motomura, pg. 2603: “Cloning and purification of class III PPK2”), the enzyme is at a concentration of 0.25 µM in the reaction. Kuroda also teaches a preference of 1 – 500 µg/ml (par. 41; for M. ruber, this would be around 0.03 – 16 µM). Therefore, the limitation that concentration be between 0.01µM – 1000µM is considered to be met.
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Piepenburg, Tavanti, and Gunderson with the teachings of Kuroda. One would have been motivated to do so because a thermophilic PPK2, such as the one from M. ruber, is heat-resistant and can more stably produce ATP from AMP (par. 16).
Claim 14 is rejected under 35 U.S.C. 103 as unpatentable over the combination of Piepenburg et al. (published July 2006; Piepenburg et al. PLoS Biol. 2006 Jul;4(7):e204), Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580), and Gunderson (published May 24, 2018; Patent Application Publication US 20180141020), as applied to claim 1 above, and further in view of Ge et al. (published Dec 8, 2011; Ge et al. PLoS One. 2011;6(12):e28707).
Piepenburg, Tavanti, and Gunderson teach the limitations of claim 1, as discussed above. Note that this 35 U.S.C. 103 rejection is distinct from the rejection documented on pg. 15-16 of this action because it relies on Piepenburg as a primary reference instead of Tavanti.
Regarding claim 14, the combined references do not explicitly teach that the composition does not comprise PEG.
Ge teaches that for the purposes of macromolecular crowding of enzymatic reactions, PEG is an equivalent of polymers such as Ficoll and dextran (pg. 2, col. 1, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to substitute PEG for a different macromolecular crowding agent such as Ficoll or dextran. One would have been motivated to do so because PEG, Ficoll, and dextran were known in the art as macromolecular crowding agents. Furthermore, one may have been motivated to substitute PEG with another crowding agent because it is known to have strong inhibitory effects on processes involving enzymes like polymerases, perhaps due to its ability to cause precipitation (pg. 7, col. 1, 1st par.)
Response to Arguments
In the response filed July 24, 2026, Applicant argued that Tavanti does not disclose, teach, or suggest the arrangement of elements recited in amended claim 1, and that Tavanti is silent as to uses of an inorganic polyphosphate and polyphosphate kinases to provide the recited improvements to clustering on a solid substrate. Applicant argued that none of the combined references (Piepenburg, Ge, Zhang, Kuroda, Motomura) correct these deficiencies.
These arguments have been fully and carefully considered. However, as a result of amendments to the claims, the modified rejections are based on a different combination of references. These combined references teach all the limitations of the amended claims. Please see the rejections above for further discussion.
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 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-15, 18, and 20-23 of co-pending Application No. 18/476,052, in view of Tavanti et al. (published June 29, 2021; Tavanti et al. ChemCatChem. 2021, 13, 3565-3580).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to compositions (ref claim 1-3, 5-13). Both sets of claims require:
a solid substrate having first and second pluralities of amplification primers coupled thereto, the first plurality of amplification primers being orthogonal to the second plurality of amplification primers (claim 1)
a nucleic acid template bound to the solid substrate through hybridization to an amplification primer of the first plurality of amplification primers (claim 1)
Amplification compositions (claim 14)
ATP-generating substrate and ATP-generating enzyme (claim 3)
Recombinase, single-stranded binding protein, polymerase, and NTPs (claim 3)
The absence of PEG (claim 6)
Resynthesis or clustering compositions (claim 1, 8)
that the polymerase is present to amplify the nucleic acid template using the NTPs and the first plurality of amplification primers (claim 1)
Although the reference patent does not explicitly require inorganic polyphosphate and a polyphosphate kinase, it would be obvious to one with ordinary skill in the art that inorganic polyphosphate and polyphosphate kinase systems are among the known systems of ATP-generating substrates and enzymes (Tavanti: Introduction).
The reference does not explicitly state that the that the polyphosphate kinase is present to increase clustering kinetics and increase sequencing signal intensity by recycling ADP to ATP using the inorganic polyphosphate, nor that amplifying the nucleic acid template generates ADP. However, compositions are analyzed with respect to their structure. Therefore, these limitations represent intended uses which do not limit the scope of the claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
In the response filed July 24, 2026, Applicant asserted that the reference application and Tavanti do not disclose, teach, or suggest the arrangement of elements recited in amended claim 1, and that they are silent as to uses of an inorganic polyphosphate and polyphosphate kinases to provide the recited improvements to clustering on a solid substrate. Applicant requested that the rejections therefore be withdrawn or held in abeyance.
These arguments have been fully considered and not found to be persuasive. The amended elements of the instant application are either present in the amended claims of the reference application (e.g. solid substrate) or are intended use or functional language which does not limit the scope of the composition/product claims. Please see the modified rejection above for further discussion.
Regarding the request to hold the claims in abeyance, the request has been fully considered. MPEP 804(I)(B)(1) states that “[a] complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers)... As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.”
Because Applicant did not file a terminal disclaimer or show that the claims subject to the rejection are patentably distinct from the reference application’s claims, the rejections are maintained.
Conclusion
No claims are allowed.
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.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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