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 .
Priority
The present application, filed on July 2, 2021 is a 371 of PCT/US2020/012358, filed on January 6, 2020 and also claims the benefit of US Provisional Application No. 62/788,614, filed on January 4, 2019.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 2, 2026 has been entered.
Claim Status and Action Summary
Claims 1-9, 11-21, and 23-25 are pending and currently under examination.
This action is in response to the papers filed March 2, 2026.
Any objections and rejections not reiterated below are hereby withdrawn.
The rejection under U.S.C. 101 has been withdrawn
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.
Claims 1-9 and 11-14 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites the limitation “wherein the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”. The instant specification provides “This enhancement in temporal resolution is… simply limited by (a) the incorporation rate of TdT, which is 1 dNTP per second under optimal conditions…” (i.e. the maximal incorporation rate of TdT under ideal conditions is 1 base per second) (Specification, page 24, paragraph 2). Furthermore, the specification demonstrates an observed “average incorporation rate of 0.17 dNTPs/minute” (i.e. approximately 1 base per 6 minutes or 0.0028 bases per second) by TdT in the presence of Mg2+ (Specification, page 8, paragraph 2, Figure 15). Additionally, the prior art, Kent et al., “Polymerase θ is a robust terminal transferase that oscillates between three different mechanisms during end-joining”, eLife 5:e13740 (2016) measure incorporation rates and processivity Pol θ under various conditions and conclude “aside from TdT, Pol θ possesses the most robust terminal transferase activity for the polymerase enzyme class.” (i.e. among the genus “template-independent DNA polymerases”, TdT was known as possessing the highest optimal incorporation rate and processivity).
Therefore, it is unclear what template-independent DNA polymerase(s) in addition to TdT is/are intended to be encompassed by the claim limitation that “the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”, as the specification and the prior art appear to teach that TdT has a maximum rate under optimal conditions of 1 base per second and under exemplary conditions in the specification, TdT exhibits much lower incorporation rates (i.e. 0.17 bases per minute).
Claim 1 recites the claim phrase “wherein the method provides temporal resolution of the biological signal recording of up to at least one 1 minute.” Temporal resolution (i.e. the limit of separation in time units between two discrete observations of a signal) increases with decreasing time required between two observations (i.e. a method that can differentiate between two signals that occur closer together in time is said to have higher temporal resolution). The claim language “up to at least one 1 minute” is indefinite because it is unclear whether a temporal resolution of 1 minute is intended to be the maximum resolution recited by the claim (i.e. the method can differentiate between two signals separated by at least 1 minute) or whether the claim is intended to encompass methods having temporal resolution of at “least” (i.e. a resolution greater than) 1 minute (i.e. the method can differentiate between two signals separated by less than 1 minute).
Claims 2-9 and 11-14 are indefinite because they depend from, and thus necessarily include the indefinite limitations of, claim 1.
Claim Interpretation
Claim 1 recites the limitation “wherein the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”. This claim limitation has been interpreted as requiring selecting a template-independent DNA polymerase having an intrinsic rate of incorporation of dNTPs into an unspecified “DNA substrate” under unspecified conditions in “an organic environment” of 1 dNTP per second or faster (i.e. “at least one base per second”).
Claim 1 recites the phrase “wherein the method provides temporal resolution of the biological signal recording of up to at least one 1 minute.”
This claim phrase has been interpreted as expressing an intended result of the process steps positively recited by the claim (exposing a template independent DNA polymerase… allowing the DNA polymerase to add dNTPs… wherein the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate… and sequencing the DNA substrate…wherein the dNTP content of the DNA substrate corresponds to the concentration of the variable…
MPEP 2111.04 states:
“The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003).”
Therefore, because the claim phrase “wherein the method provides temporal resolution of the biological signal recording of up to at least one 1 minute” simply expresses the intended result of the positively recited method steps, it has not been given weight herein.
Claim Rejections - 35 USC § 112(a)-Written Description
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.
Claim 1 is rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention.
This is a new matter rejection.
Claim 1 as amended encompasses methods requiring a “template-independent DNA polymerase… wherein the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”.
The response asserts that support for the amendments can be found at paragraphs 70 and 72 in the specification. These citations have been thoroughly reviewed, however, no reference to a template-independent DNA polymerase having an incorporation rate greater than 1 base per second is present in the specification. Therefore, the genus “a template-independent DNA polymerase…[that] incorporates at least one base per second…” constitutes new matter. Applicant is required to cancel the new matter in the reply to this Office Action.
Claims 1-9 and 11-14 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention.
Claim 1 encompasses a genus of unspecified template-independent DNA polymerases defined by their function “incorporates at least one base per second into the DNA substrate”.
The instant specification identifies TdT as an exemplary template-independent DNA polymerase, which is disclosed as having an incorporation rate of is 1 dNTP per second under optimal conditions…” (i.e. the maximal incorporation rate of TdT under ideal conditions is 1 base per second) (Specification, page 24, paragraph 2). Furthermore, the specification demonstrates an observed “average incorporation rate of 0.17 dNTPs/minute” (i.e. approximately 1 base per 6 minutes or 0.0028 bases per second) by TdT in the presence of Mg2+ (Specification, page 8, paragraph 2, Figure 15). Additionally, the prior art, Kent et al., “Polymerase θ is a robust terminal transferase that oscillates between three different mechanisms during end-joining”, eLife 5:e13740 (2016) measure incorporation rates and processivity of Pol θ under various conditions and conclude “aside from TdT, Pol θ possesses the most robust terminal transferase activity for the polymerase enzyme class.” (i.e. among the genus “template-independent DNA polymerases”, TdT was known as possessing the highest optimal incorporation rate and processivity).
Therefore, it is unclear what template-independent DNA polymerase(s) in addition to TdT is/are intended to be encompassed by the claim limitation that “the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”, as the specification and the prior art appear to teach that TdT has a maximum rate under optimal conditions of 1 base per second and under exemplary conditions in the specification, TdT exhibits much lower incorporation rates (i.e. 0.17 bases per minute).
Relevant to the lack of particular structural or methodological limitations or identification of any members of the genus “template-independent DNA polymerase… wherein the… DNA polymerase incorporates at least one base per second…”, MPEP 2163 states:
“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 inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
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) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.) On the other hand, there may be situations where one species adequately supports a genus. See, e.g., Rasmussen, 650 F.2d at 1214, 211 USPQ at 326-27 (disclosure of a single method of adheringly applying one layer to another was sufficient to support a generic claim to "adheringly applying" because one skilled in the art reading the specification would understand that it is unimportant how the layers are adhered, so long as they are adhered); In re Herschler, 591 F.2d 693, 697, 200 USPQ 711, 714 (CCPA 1979) (disclosure of corticosteroid in DMSO sufficient to support claims drawn to a method of using a mixture of a "physiologically active steroid" and DMSO because "use of known chemical compounds in a manner auxiliary to the invention must have a corresponding written description only so specific as to lead one having ordinary skill in the art to that class of compounds. Occasionally, a functional recitation of those known compounds in the specification may be sufficient as that description."); In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 285 (CCPA 1973) (the phrase "air or other gas which is inert to the liquid" was sufficient to support a claim to "inert fluid media" because the description of the properties and functions of the air or other gas segmentizing medium would suggest to a person skilled in the art that appellant’s invention includes the use of "inert fluid" broadly.). See Juno, 10 F.4th 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) (where the claims are directed to species that bind to various selected targets, it is not fatal that all species are not disclosed as long as the patent provides other means of identifying which species would possess the claimed common structural characteristics or shared traits).
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). The issue is whether a person skilled in the art would understand inventor to have invented, and been in possession of, the invention as broadly claimed. In LizardTech, claims to a generic method of making a seamless discrete wavelet transformation (DWT) were held invalid under 35 U.S.C. 112, first paragraph, because the specification taught only one particular method for making a seamless DWT and there was no evidence that the specification contemplated a more generic method. Id.; see also Tronzo v. Biomet, 156 F.3d at 1159, 47 USPQ2d at 1833 (Fed. Cir. 1998)(holding that the disclosure of a species in a parent application did not provide adequate written description support for claims to a genus in a child application where the specification taught against other species).
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.). Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. For example, in the molecular biology arts, if an applicant disclosed an amino acid sequence, it would be unnecessary to provide an explicit disclosure of nucleic acid sequences that encoded the amino acid sequence. Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994). If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph.”
The present claims broadly encompass methods comprising exposing “a template-independent DNA polymerase… [that] incorporates at least one base per second into [a] DNA substrate”.
In the case of the instant claims, the functionality “incorporates at least one base per second…” is a critical feature of the claimed method.
The specification teaches only TdT as a member of the genus “template-independent DNA polymerase” and that “TdT” incorporates 1 dNTP/second under optimal conditions (i.e. does not incorporate more than 1 base per second).
The specification does not teach any template-independent DNA polymerase that is shown to “incorporate [more than] one base per second…”.
While the skilled artisan may be capable of identifying template-independent polymerases with the claimed functionality of “incorporating at least one base per second”, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Thus, considering the breadth of the compounds required by the claimed methods, their specific required functionality, and the teachings of the instant specification, it is the conclusion of the examiner that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
Claims 1-9 and 11-14 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for “a template-independent DNA polymerase [that] incorporates up to one base per second”, does not reasonably provide enablement for “a template-independent DNA polymerase [that] incorporates at least one base per second”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112(a) have been described by the court in In re Wands, 8 USPQ2d 1400 (CAFC 1988). Wands states at page 1404, “Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and breadth of the claims
Claim 1 broadly encompasses a method comprising a use of any of a genus of “template-independent DNA polymerase[s]” defined by their rate of incorporation of bases (i.e. dNTPs) into a DNA substrate “wherein the template-independent DNA polymerase incorporates at least one base per second into the DNA substrate”. Therefore, the broadest reasonable interpretation encompasses the use of any member of this genus (including modified or mutant enzymes) exhibiting the recited kinetic properties for incorporating any generic “base” into any generic “DNA substrate” in any generic “organic environment”.
The state of the art
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co, 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The prior art teaches “Aside from TdT, Polθ possesses the most robust terminal transferase activity for the polymerase enzyme class” (Kent et al., page 15, paragraph 1).
Furthermore, post-filing date art, Kuznetsova et al., “Insight into the mechanism of DNA synthesis by human terminal deoxynucleotidyltransferase” Life Science Alliance Vol 5, no 12, e202201428 (published 2022) summarizes observed rate constants of accumulation of products having one additional nucleotide (i.e. time per incorporation of a single base into a DNA substrate) by human TdT vary by nucleotide identity and by the presence of metal cations (Mg2+ or Mn2+) wherein the fastest incorporation of one nucleotide required at least 10 seconds (Kuznetsova et al., page 6, column 1 and table 1).
Additionally, applicant’s own post-filing date publication, Bhan et al., “Recording Temporal Signals with Minutes Resolution Using Enzymatic DNA synthesis” J. Am. Chem. Soc. 2021, 143, 16630-16640 teach methods for identifying biological signals comprising exposing TdT to an organic environment to identify fluctuation in concentrations of cobalt, calcium, and zinc ions to within 1 minute (i.e. with a resolution of approximately 1 minute), and “engineer TdT to allosterically turn off in the presence of a physiologically relevant concentration of calcium” (Bhan et al., 2021, Abstract).
Guidance in the specification and working examples
The specification teaches “temporal resolution… is limited by the incorporation rate of TdT, which is 1 dNTP per second under optimal conditions” (specification, page 24, paragraph 1) (i.e. the maximum rate of incorporation observed for TdT (the “most robust terminal transferase” known at the time of filing) is 1 base per second).
The specification teaches “TURTLES has the capability to record multiple fluctuations. This allows for the estimation of the rise and fall of an input signal (such as a Co2+ pulse) to within three minutes” (i.e. a resolution of ~3 minutes) (Specification, page 18, paragraph 2).
The specification teaches an example where “the technology was able to successfully record a step change of 10 minutes time-scale with a resolution of about 1 minute” (Specification, page 22, paragraph 2).
The specification does not teach any examples wherein: 1) a template-independent polymerase incorporates more than one base per second or 2) the method provides temporal resolution (greater than) 1 minute (i.e. resolution of signals separated in time by less than one minute).
Therefore, it is not clear what polymerases, if any, were known at the filing date with kinetic properties exceeding TdT (with a maximum rate of incorporation under ideal conditions, i.e. not in a neuron or tissue sample of 1 nucleotide per second); furthermore, it is unclear how the claimed method is intended to achieve resolution greater than (i.e. “up to at least”) 1 minute. As such, the selection/discovery/design of a “template-independent DNA polymerase” having properties recited in the present claims is not predictable based upon the teachings and examples present in the specification.
Quantity of Experimentation
Claim 1 is broadly drawn to a method requiring the use of a template-independent DNA polymerase capable of incorporating at least one nucleotide per second into a DNA substrate in “an organic environment” wherein the method provides temporal resolution up to at least one minute (i.e. encompassing methods exceeding a resolution of 1 minute; capable of distinguishing between signals separated by less than one minute in time).
The specification teaches no template-independent DNA polymerases having properties commensurate with the full scope of the claims (i.e. no polymerase capable of incorporating more than one nucleotide per second and no method having temporal resolution exceeding one minute).
The art teaches that TdT has a maximal rate of incorporation of nucleotides into a DNA substrate of 1 nucleotide per second under ideal biochemical conditions.
Therefore, it is unpredictable that the skilled artisan could: identify, discover, or design a template-independent DNA polymerase having the properties broadly claimed by the present claims.
The quantity of experimentation in this area is large, since there is no guidance in the specification or art that supports “a template-independent DNA polymerase [that] incorporates [more than] one base per second into a DNA substrate” under ideal conditions, much less in any “organic environment” or “the inside of a cell” or “the extracellular space between cells in a tissue or organ” as presently claimed. Furthermore, there is no demonstration of a method as presently claimed having a temporal resolution in excess of one minute.
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
In the instant case, given the breadth of the claim to a method encompassing the use of an undefined template-independent DNA polymerase with the broadly recited properties “incorporates at least one base per second…” and “provides temporal resolution… up to at least one minute”, the lack of guidance provided in the specification and prior art as to what template-independent DNA polymerase(s) are capable of incorporating nucleotides at a rate exceeding one nucleotides per second under ideal conditions, the large quantity of experimentation that would be necessary to discover or produce an enzyme having the properties required by the broad claims, lack of demonstrated working examples commensurate with the breadth of the instant claims, and the unpredictability of the art, balanced only against the high level of skill in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of claim 1 as broadly written.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9, 11-13, 15-21, and 24-25 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Zamft et al., “Measuring Cation Dependent DNA Polymerase Fidelity Landscapes by Deep Sequencing” PLoS ONE 7(8): e43876 (2012) in view of Kent et al., “Polymerase θ is a robust terminal transferase that oscillates between three different mechanisms during end-joining”, eLife 5:e13740 (2016) and Sheth et al., “DNA-based memory devices for recording cellular events”, Nature Reviews Genetics (2018).
Regarding claim 1, Zamft teaches a method of identifying a biological signal comprising exposing an “ion-sensitive DNA polymerase” to an environment comprising dNTPs, a DNA substrate, and a variable, and isolating and sequencing the DNA substrate to measure the concentration of the variable in the environment (Zamft, Figure 1). Specifically, Zamft teaches a method of recording biological signals into a known DNA template wherein the error rate of the DNA polymerase measures the concentration of a cation over time (Zamft, Abstract). Furthermore, Zamft teaches determining the dNTP content of the substrate by “deep sequencing” (Zamft, page 6, column 2, paragraph 2).
Zamft does not teach that the “ion-sensitive DNA polymerase” is a template-independent DNA polymerase.
However, Sheth teaches DNA-based recording techniques including so-called “polymerase ticker tape” methodologies, such as those taught by Zamft (Sheth table 1) may be improved by biochemical steps to write DNA directionally with single base pair resolution with high efficiency and sensitivity (Sheth, page 729, column 2, paragraph 5). Further, Sheth explicitly contemplates non-templated polymerases and terminal deoxynucleotidyl transferases (TdTs) should be leveraged for improved recording applications (Sheth, page 730, column 1, paragraph 1).
Additionally, Kent teaches two non-templated DNA polymerases (Terminal deoxynucleotidyl transferase (TdT), and Polymerase θ) have similar activity to extend single stranded DNA (Kent, page 17, paragraph 2), and are sensitive to the concentration of several cations (Kent, figure 1E).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of recording biological signals into a DNA substrate using a template-dependent “ion-sensitive DNA polymerase”, taught by Zamft, by substituting the ion-sensitive, template-dependent DNA polymerase with an ion-sensitive, template-independent DNA polymerase such as a TdT, as taught by Kent and Sheth. The ordinary artisan would have been motivated to substitute a template-independent DNA polymerase in place of the template dependent polymerase in the method taught by Zamft because of the teaching of Sheth that template-independent polymerases such as TdTs should be leveraged for next-generation recording applications (Sheth, page 730, column 1, paragraph 1).
Regarding claim 2, Sheth teaches a template-independent DNA polymerase for DNA recording applications is a TdT (Sheth, page 730, column 1, paragraph 1).
Regarding claim 3, Zamft teaches the dNTP content of the DNA substrate varies with cation concentration in a cell (Zamft, figure 1 and page 6, column 1, paragraph 1).
Regarding claim 4, Sheth teaches “a proposed polymerase-based ticker tape… can be made sensitive to a signal of interest, such as ion concentrations during recording of neuronal activity.” (Sheth, page 723, column 2, paragraph 3)
Regarding claim 5, Sheth teaches both intracellular and extracellular variables, such as electrochemical gradients (i.e. cation concentrations) can be inputs for sensing and recording (Sheth, page 719, column 2, paragraph 2).
Regarding claim 6, Zamft, or alternatively Kent, teaches the variable is a cation (Zamft, figure 2 or Kent, figure 1E).
Regarding claim 7, Kent teaches template-independent terminal transferase activity (i.e. the resulting dNTP content of the DNA substrate) varies with cation concentrations including Co2+. (Kent, figure 1E).
Regarding claim 8, Kent teaches the DNA substrate is a single stranded DNA. (Kent, figure 1E and corresponding caption; page 3)
Regarding claim 9, Zamft teaches determining the dNTP content of the substrate by “deep sequencing” (Zamft, page 6, column 2, paragraph 2) using Illumina sequencing (Zamft, page 8, column 2, paragraph 5).
Regarding claim 11, Zamft teaches recording cation concentration in the sequence of a DNA substrate (Zamft, abstract).
Regarding claims 12-13, Sheth teaches directional writers (i.e. non-templated DNA polymerases) record temporally changing biological signals and polymerase error rates can be made sensitive to a signal of interest, such as ion concentrations during recording of neuronal activity, thus allowing for temporal encoding of these signals onto DNA memory substrates (i.e. absolute or relative concentrations over time) (Sheth, page 723, column 2, paragraph 3).
Regarding claim 15, Zamft teaches the dNTP content (i.e. the sequence) of the DNA substrate varies with cation concentration in a cell (Zamft, figure 1 and page 6, column 1, paragraph 1).
Regarding claim 16, Sheth teaches a template-independent DNA polymerase for DNA recording applications is a TdT (Sheth, page 730, column 1, paragraph 1).
Regarding claim 17, Sheth teaches “a proposed polymerase-based ticker tape… can be made sensitive to a signal of interest, such as ion concentrations during recording of neuronal activity.” (i.e. the cell is a neuron) (Sheth, page 723, column 2, paragraph 3).
Regarding claim 18, Zamft teaches the dNTP content of the DNA substrate varies with cation concentration in a cell (Zamft, figure 1 and page 6, column 1, paragraph 1).
Regarding claim 19, Kent teaches template-independent terminal transferase activity (i.e. the resulting dNTP content of the DNA substrate) varies with cation concentrations including Co2+. (Kent, figure 1E).
Regarding claim 20, Kent teaches the DNA substrate is a single stranded DNA (Kent, figure 1E and corresponding caption; page 3).
Regarding claim 21, Zamft teaches determining the dNTP content of the substrate by “deep sequencing” (Zamft, page 6, column 2, paragraph 2) using Illumina sequencing (Zamft, page 8, column 2, paragraph 5).
Regarding claims 24-25, Sheth teaches directional writers (i.e. non-templated DNA polymerases) record temporally changing biological signals and polymerase error rates can be made sensitive to a signal of interest, such as ion concentrations during recording of neuronal activity, thus allowing for temporal encoding of these signals onto DNA memory substrates (i.e. absolute or relative concentrations over time) (Sheth, page 723, column 2, paragraph 3).
Response to arguments
The response traverses the 103 rejection above on the grounds that the teaching/suggestion of Sheth that template-independent polymerases such as TdTs should be leveraged for next-generation recording applications because the response asserts that the disclosure of Sheth is not enabling for detection of a change in a variable (i.e. cations) within a cell comprising exposing a template-independent DNA polymerase within a cell to dNTPs and a variable. Furthermore, the response argues that Zamft teaches recording information into DNA sequences using a known template dependent on the cation concentration dependent misincorporation rate activity of template-dependent DNA polymerases, and that replacing the DNA polymerase of Zamft with TdT as taught by Sheth would render the device (method) of Zamft inoperable for its intended purpose.
These arguments have been thoroughly reviewed and are not persuasive.
Regarding the assertion that the teaching/suggestion/motivation of Sheth is not enabling, MPEP 2121 (bold emphasis added) states:
When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). Specifically, in In re Antor Media Corp., the court stated:
"Consistent with the statutory framework and our precedent, we therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling. As long as an examiner makes a proper prima facie case of anticipation by giving adequate notice under § 132, the burden shifts to the applicant to submit rebuttal evidence of nonenablement."
In re Antor Media Corp., 689 F.3d at 1289, 103 USPQ2d at 1559.
Where a reference appears to not be enabling on its face, however, an applicant may successfully challenge the cited prior art for lack of enablement by argument without supporting evidence. In re Morsa, 713 F.3d 104, 110, 106 USPQ2d 1327, 1332 (Fed. Cir. 2013).
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See also MPEP § 716.07.
Furthermore, regarding the citation of Sheth as prior art in the 103 (obviousness) rejection of record, the MPEP states:
"In determining that quantum of prior art disclosure which is necessary to declare an ... invention ‘not novel’ or ‘anticipated’ within section 102, the stated test is whether a reference contains an ‘enabling disclosure’... ." In re Hoeksema, 399 F.2d 269, 158 USPQ 596 (CCPA 1968). The disclosure in an assertedly anticipating reference must provide an enabling disclosure of the desired subject matter; mere naming or description of the subject matter is insufficient, if it cannot be produced without undue experimentation. Elan Pharm., Inc. v. Mayo Found. For Med. Educ. & Research, 346 F.3d 1051, 1054, 68 USPQ2d 1373, 1376 (Fed. Cir. 2003) (At issue was whether a prior art reference enabled one of ordinary skill in the art to produce Elan’s claimed transgenic mouse without undue experimentation. Without a disclosure enabling one skilled in the art to produce a transgenic mouse without undue experimentation, the reference would not be applicable as prior art.). A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the effective filing date of the claimed invention for applications or patents subject to the first inventor to file provisions of the AIA or at the time the invention was made for applications or patents subject to pre-AIA law. "Such possession is effected if one of ordinary skill in the art could have combined the publication’s description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
II. 35 U.S.C. 103 REJECTIONS AND USE OF INOPERATIVE PRIOR ART
"Even if a reference discloses an inoperative device, it is prior art for all that it teaches." Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989). Therefore, "a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103." Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569, 1578, 19 USPQ2d 1241, 1247 (Fed. Cir. 1991).
Therefore, the assertion that the suggestion of Sheth that TdTs should be leveraged for improved recording applications is not persuasive in the absence of evidence that the disclosure of Sheth is not enabling without additional undue experimentation (i.e. that “one of ordinary skill in the art could not have combined the publication’s description of the invention with their own knowledge to make the claimed invention”.
Regarding the argument that the teaching/suggestion/motivation provided by Sheth would have rendered the methods of Zamft inoperable for their intended purpose, the intended purpose of Zamft (similar to the claimed invention) is to measure changing ion concentrations in live cells by observing the ion-concentration influenced enzymatic activity of a DNA polymerase. Sheth specifically references the methods taught by Zamft (see table 1, reproduced below for convenience) and suggests that an ideal recording system would consist of steps to write DNA with single base pair resolution in a directional manner and that can be robustly modulated. Furthermore, Sheth specifically names TdTs as known enzymes with desirable properties expected to improve the templated methods taught by Zamft.
Therefore, it is the position of the examiner that: Sheth is presumed to be enabling for all that it teaches absent any evidence to the contrary (i.e. evidence that one of ordinary skill in the art could not have performed the substitution of a TdT into the method of Zamft as suggested by Sheth without additional undue experimentation).
The response filed with the request for continued examination asserts that “although Sheth suggests using template-independent polymerases, the suggestion is entirely speculative. Sheth fails to provide any working examples of template-independent polymerases, and instead theorizes suitable polymerases “almost certainly exist in nature” and “should be investigated and leveraged for next-generation recording applications.” Such a conclusory suggestion would not provide a reasonable expectation of successfully achieving the type of temporal resolution provided by the presently claimed methods, and therefore the claims should be considered non-obvious.”
These assertions have been considered and are not persuasive. As the response correctly states, Sheth does indeed suggest the use of “template-independent polymerases” in so-called ticker-tape assays for recording fluctuations of ion concentrations into a DNA substrate. However, Sheth does not simply theorize that suitable polymerases exist in nature, but rather specifically name terminal deoxynucleotidyl transferase (TdT) as a non-templated polymerase having suitable properties. Furthermore, the assertion that the resolution achieved by the claimed method comprising the substitution of TdT for template-dependent polymerases suggested by Sheth achieves unexpected results is not persuasive at least because TdT has long had a known optimal rate equivalent to that taught as a limiting factor in the instant specification (one nucleotide per second; see Kent et al., page 15, paragraph 1; Kuznetsova et al., page 6, column 1 and table 1; and the instant specification, page 24, paragraph 1). Furthermore, MPEP 716.02(d), regarding assertions of unexpected results, states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. While the claims exceed the range of polymerization rates attainable by the widely known and specifically suggested template-independent DNA polymerase TdT, there is no evidence in the specification that is commensurate in scope with broad claims “wherein the template-independent DNA polymerase incorporates at least (i.e. encompassing more than) one base per second into the DNA substrate” or “the method provides temporal resolution… up to at least (i.e. encompassing shorter time spans; greater resolution) one minute”.
For all of the reasons of record and those discussed above, the 103 rejection is maintained.
Claims 14 and 23 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Zamft et al., “Measuring Cation Dependent DNA Polymerase Fidelity Landscapes by Deep Sequencing” PLoS ONE 7(8): e43876 (2012) in view of Kent et al., “Polymerase θ is a robust terminal transferase that oscillates between three different mechanisms during end-joining”, eLife 5:e13740 (2016) and Sheth et al., “DNA-based memory devices for recording cellular events”, Nature Reviews Genetics (2018) as applied to claims 1-9, 11-13, 15-21, and 24-25, and further in view of Cybulski et al., “Nucleotide-time alignment for molecular recorders” PLoS Comput Biol 13(5):e1005483 (2017).
Regarding claims 14 and 23, Zamft et al. in view of Kent et al. and Sheth et al. teaches a method of identifying a change in a variable in a cell comprising exposing a template-independent DNA polymerase and a single stranded DNA substrate to the variable, allowing the polymerase to add nucleotides to the substrate, and measure the concentration of the variable in the environment (see 103 rejections of claims 1 and 15 above).
Zamft et al. in view of Kent et al. and Sheth et al. does not teach using a hidden Markov model to assign the most likely cation state at each base.
However, Cybulski et al. teach a method comprising using a DNA polymerase to record intracellular calcium concentrations comprising using a “Dynamic Time Warping-based algorithm” to estimate the time when each nucleotide was incorporated. (Cybulski et al., abstract) Cybulski et al. teaches that the algorithm comprises a hidden Markov model (Cybulski et al, page 15, paragraph 2). Cybulski teaches that this algorithm “aligns a single DNA-based record to an estimate of neural activity.” (Cybulski et al, page 4, paragraph 1) Finally, Cybulski et al. teach that the model relates cation concentration to polymerase error rate, incorporation rate, and pausing. (Cybulski et al, page 4, paragraph 3)
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of recording cation concentrations in a cell onto a single stranded nucleic acid template using a cation-sensitive template-independent DNA polymerase, taught by Zamft et al. in view of Kent et al. and Sheth et al. by further using the “Dynamic Time Warping-based algorithm” comprising a hidden Markov model to estimate the time when each nucleotide was incorporated and relate the dNTP content of the substrate to the cation concentration at each time point, as taught by Cybulski et al. The ordinary artisan would have been motivated to apply the algorithm taught by Cybulski et al. to the method taught by Zamft et al. in view of Kent et al. and Sheth et al. because of the teaching of Cybulski “Perhaps most importantly, we have shown that, should a DNAP with certain properties be developed, we can provide temporal indexing to its output and capture neural behaviors using a molecular recording approach” (Cybulski et al, page 14, paragraph 2) The ordinary artisan would therefore have been reasonably confident that the algorithm taught by Cybulski et al. would have successfully associated the dNTP content of the “ticker tape” substrate transcribed by the method of Zamft et al. in view of Kent et al. and Sheth et al. with the amount of a variable in the cell during said transcription.
Response to arguments
The response argues that the teachings of Cybulski does not compensate for the alleged deficiencies of Zamft in view of Kent and Sheth. This argument is not persuasive for the reasons discussed above.
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.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12 of copending Application No. 17/687,276 (herein referred to as ‘276). Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 12 of ‘276 renders obvious Claim 1.
Claim 12 of ‘276 recites exposing a DNA-synthesis based recording system comprising a TdT to an organic environment comprising dNTPs and a variable, allowing the TdT to add dNTPs to a DNA substrate, and isolating the DNA substrate. Claim 12 of ‘276 does not recite any particular method for reading or decoding “the dNTP content of the DNA substrate [that] corresponds to the concentration of the variable”.
However, Zamft teaches a method of identifying a biological signal comprising exposing an “ion-sensitive DNA polymerase” to an environment comprising dNTPs, a DNA substrate, and a variable, and isolating and sequencing the DNA substrate to measure the concentration of the variable in the environment (Zamft, Figure 1). Specifically, Zamft teaches a method of recording biological signals into a known DNA template wherein the error rate of the DNA polymerase measures the concentration of a cation over time (Zamft, Abstract). Furthermore, Zamft teaches determining the dNTP content of the substrate by “deep sequencing” (Zamft, page 6, column 2, paragraph 2).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art to have modified the method recited by claim 12 of ‘276 comprising exposing cells that comprise a TdT to an organic environment, dNTPs, a variable, and a DNA substrate, isolating the DNA substrate, wherein the dNTP content of the DNA substrate corresponds to the concentration (i.e. presence) of the variable in the environment to further comprise a step of determining the dNTP content of the substrate by sequencing the substrate.
The ordinary artisan would have been motivated to sequence the DNA substrate to retrieve the encoded information corresponding to the concentration of the variable because of the express teachings of Zamft that such “ticker tape” encoding systems can readily be sequenced to obtain said information (Zamft, page 7, column 2).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
The response requests reconsideration of the double-patenting rejection in view of the amended claims and in view of the arguments above against obviousness over Zamft. The amendments to the claims and arguments regarding the teachings of Zamft have been considered and are not persuasive. The present claims include open “comprising” claim language and recite exposing a template-independent DNA polymerase to an organic environment comprising dNTPs and a variable, that in particular embodiments recited by dependent claims, is a cell. Claim 1 of ‘276 comprises additional limitations in addition to “a terminal deoxynucleotidyl transferase (TdT)”, which is a template-independent DNA polymerase having properties within the ranges required by the amended claim 1. Because of: a) the open claim language of present claim 1 encompasses the narrower scope of claim 1 of ‘276; b) the teachings of Zamft discussed above comprising methods of “reading” the outputs of DNA-synthesis based recording (i.e. DNA ticker-tape) systems comprising isolating the DNA template and sequencing the DNA substrate to determine the concentration of the variable in the organic environment; and c) the reasons discussed at length above regarding the obviousness of the present claim(s) over the cited references; these arguments are not persuasive.
Conclusion
No claim is allowed.
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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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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