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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 Jan 2026 has been entered.
Claim Status
The claim set filed 20 Jan 2026 is acknowledged. Claims 1 and 10-11 are currently pending. Of those, all claims were previously presented. Claims 2-9 and 12 are cancelled. Claims 1 and 10-11 will be examined on the merits herein.
References to the specification in this action will use paragraph numbers from the Pre-Grant Publication US20210355434A1.
Response to Arguments
The Applicants’ arguments filed 20 Jan 2026 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Final Office Action mailed 17 Oct 2025 will be referred to as “FOA.”
Rejection(s) Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(a)
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 and 10-11 remain 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.
Regarding claim 1, the claim has been amended to recite a Vibrio natriegens bacteria modified by homologous recombination in chromosome 1 specifically, by the insertion of one or more polypeptides selected from a group consisting of geranylpyrophosphate:olivetolate geranyltransferase (GOT), tetraketide synthase (TKS), olivetolic acid cyclase (OAC). Applicant pointed to previously presented claim 4 and para. [0017] as support for this homologous recombination occurring in chromosome 1, and argues that “The paragraph clearly indicates that chromosome 1 is contemplated as a target site for genetic modification, including relocation or incorporation of functional genes using homologous recombination.” (Remarks 4/15/2025 pg. 5). Para. [0017] was copied in the Remarks (4/15/2025 pg. 4-5) and copied in part below:
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The examiner disagrees that [0017] provides support for one or more of GOT, TKS, and OAC being inserted into chromosome 1 specifically. Instead, [0017] only provides support for altering chromosome 1 to contain “the essential elements from chromosome 2”, and for generically “knocking in appropriate genes” without a disclosed target location. There is no evidence of record, and applicant has not argued, that one or more of GOT, TKS, and OAC are included within “the essential elements from chromosome 2” disclosed at [0017].
Further, a mere disclosure to introduce heterologous nucleic acids including GOT, TKS, and OAC into the host microorganism as in [0013-0014] is not sufficient support for making mutations at a particular location (chromosome 1). MPEP 2163 and the courts have been clear that the introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. For example, In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) decided that an adequate description of a genus may not support claims to a subgenus or species within the genus. Also, applicant was not entitled to the benefit of a parent filing date when the claim was directed to a subgenus (a specified range of molecular weight ratios) where the parent application contained a generic disclosure and a specific example that fell within the recited range because the court held that subgenus range was not described in the parent application. In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971). The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112.
In this case, as in Smith and Lukach, the specification disclosed a generic limitation (insertion of the GOT, TKS, and/or OAC genes at any site [0013-0014]), but this is not enough to support the claimed subset of the genus (inserting at chromosome 1 specifically). This is particularly true because, unlike in Lukach, there was not a reduction to practice of a specific example within the recited range. Therefore, one of ordinary skill in the art at the time of filing would consider that the specification does not provide adequate support for a claim limitation requiring homologous recombination occur in chromosome 1 specifically. Claims 1 and 10-11 lack support because they each recite this limitation.
Response to Arguments
Applicant argues (Remarks pg. 3-4) that:
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These arguments have been carefully considered and are not found persuasive. The Examiner agrees that par. [0013] describes chromosome 1 being modified to incorporate genetic material from chromosome 2, and describes “free” chromosome 2 “as a vector for cloning large DNAs/pathways”. This does not provide support for the claimed insertion of one or more polypeptides selected from a group consisting of geranylpyrophosphate:olivetolate geranyltransferase (GOT), tetraketide synthase (TKS), olivetolic acid cyclase (OAC) into chromosome 1 because GOT, TKS, and OAC are not genetic material from chromosome 2; they are heterologous nucleic acids as disclosed in [0014] and admitted in the Remarks. The argument that the specification “does not preclude modifications to Chromosome 1” is not relevant because an argument that the claimed invention doesn’t teach that the claimed invention cannot be made is an argument about enablement, not written description. See MPEP 2163: “This [written description] requirement is separate and distinct from the enablement requirement. … In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description").”
The Examiner agrees that par. [0014] describes “heterologous nucleic acids disclosed herein encoding one or more polypeptides disclosed herein can be introduced into host microorganisms”, but the paragraph has no disclosure of introducing the nucleic acids specifically into chromosome 1 as claimed.
The specification discusses using V. natriegens comprising a single chromosome, but does not define the term “chromosome 1” to apply to when V. natriegens comprises a single chromosome. Instead, [0017] uses a different term (“a single chromosome”) to refer to the V. natriegens chromosome in that situation. As stated in the rejection above, “The examiner disagrees that [0017] provides support for one or more of GOT, TKS, and OAC being inserted into chromosome 1 specifically. Instead, [0017] only provides support for altering chromosome 1 to contain “the essential elements from chromosome 2”, and for generically “knocking in appropriate genes” without a disclosed target location.”
Applicant argues (Remarks pg. 4-5) that
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This argument has been carefully considered but is not persuasive. 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." The declaration is not part of the specification as originally filed, so arguments and evidence about alleged improvements in performance that are first presented in a declaration are not relevant for written description.
The examiner agrees that the specification as originally filed provides support for chromosome 1 having insertions of genes from chromosome 2, and that it provides support for generic insertions of cannabinoid genes into the chromosome. This disclosure may render the modification to chromosome 1 obvious, in view of the finite number of possible chromosomes that could be chosen. However, see MPEP 2163: “The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112. See Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405.” Instead, “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention. See, e.g., Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1323, 56 USPQ2d 1481, 1483 (Fed. Cir. 2000)… An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004)”.
The applicant has not argued that the specification provided any of the above options for clearly describing the claimed invention. Therefore, applicant’s argument that the instant specification is “Unlike Smith and Lukach, where the specifications lacked specific details about the claimed subgenus” is not found persuasive. The examiner remains of the opinion from the rejection above: “In this case, as in Smith and Lukach, the specification disclosed a generic limitation (insertion of the GOT, TKS, and/or OAC genes at any site [0013-0014]), but this is not enough to support the claimed subset of the genus (inserting at chromosome 1 specifically). This is particularly true because, unlike in Lukach, there was not a reduction to practice of a specific example within the recited range. Therefore, one of ordinary skill in the art at the time of filing would consider that the specification does not provide adequate support for a claim limitation requiring homologous recombination occur in chromosome 1 specifically.”
Response to Declaration
The declaration under 37 CFR 1.132 filed 20 Jan 2026 is insufficient to overcome this rejection because: it does not include any arguments addressing written description or support for the claims in the specification as filed.
The rejection is maintained for the reasons of record and the reasons herein.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 10-11 remain rejected under 35 U.S.C. 103 as being unpatentable over Philippe et al. (US-20220002764-A1, filed 14 Nov 2019; hereafter Philippe; PTO-892 mailed 9 Jan 2024) in view of Pfeifer et al. (2019; hereafter Pfeifer; PTO-892 mailed 9 Jan 2024) and Rudenko et al. (US-20180320209-A1; hereafter Rudenko; PTO-892).
Regarding claim 1, Philippe teaches prokaryotic recombinant cells that express heterologous enzymes involved in cannabinoid biosynthesis [Abstract] (i.e. bacteria altered by the insertion of heterologous nucleic acids encoding polypeptides). Philippe teaches that the heterologous enzymes can be expressed from plasmids or bacterial artificial chromosomes, or may be chromosomally integrated [0055] (i.e. bacteria with altered chromosomes wherein the alterations comprise insertions). Specifically, Philippe teaches the microbe can be Vibrio natriegens [0058]. Philippe discloses that the microbial cell can produce cannabinoids from hexanoic acid [0007, 0018] (i.e. the genetically modified bacterium is engineered to consume hexanoic acid as a precursor to produce a cannabinoid). Philippe discloses that the biological pathway converts hexanoic acid to hexanoyl-CoA, then into cannabinoid precursors such as olivetolic acid, and finally into cannabinoids [Figure 2].
Philippe teaches “the host cell recombinantly expresses a prenylating enzyme having cannabigerolic acid synthase (CBGAS) and/or cannabigerovarinic acid synthase (CBGVAS) activity, central enzymes for the biosynthesis of all cannabinoids, and one or more additional enzymes, such as … olivetolic acid cyclase (OAC)… that increase the availability of CBGAS reactants.” [0008, emphasis added].
Regarding claim 10, Philippe discloses that the microbial cell can produce the cannabinoid from hexanoic acid [0007, 0018]. Philippe discloses that the biological pathway converts hexanoic acid to hexanoyl-CoA, then into cannabinoid precursors such as olivetolic acid, and finally into cannabinoids [Figure 2].
Regarding claim 11, Philippe discloses specific enzymes that are used for each step of this pathway, such as acyl-activating enzyme (AAE), also called hexanoyl-CoA synthetase, that synthesizes hexanoyl-CoA from hexanoate and CoA [0043]. As disclosed in Figure 2, the reaction catalyzed by this enzyme is part of the cannabinoid biosynthetic pathway and so the enzyme has the same activity as itself. Philippe also discloses using other enzymes from the cannabinoid biosynthetic pathway, such as at [0041-0042, 0044-0046, and 0049-0052].
Philippe does not teach engineered Vibrio natriegens are generated by insertion to a region in the genome using a homologous recombination vector, as in claim 1. (It is silent on the method used). Philippe also does not teach that the insertion is into chromosome 1 specifically, as in claim 1.
Regarding claim 1, Pfeifer teaches that “the fast-growing marine bacterium Vibrio natriegens represents an emerging strain for molecular biology and biotechnology” and further creates a prophage-free variant of V. natriegens that improved the robustness of the prophage-free variant toward DNA-damaging conditions, reduced cell lysis under hypo-osmotic conditions, increased pyruvate production compared to wild-type levels, and the prophage-free strain outcompeted the wild type in a competitive growth experiment (Abstract). Pfeifer teaches that the V. natriegens genome consists of two bacterial chromosomes (pg. 2 par. 5). Pfeifer teaches that the modifications performed in the study used homologous recombination to perform chromosomal deletions and chromosomal integrations, and that the protocol used for the homologous recombination had been previously described in multiple prior references (pg. 12 par. 1-2). Therefore, Pfeifer teaches an engineered V. natriegens bacteria with improved properties for biotechnological applications generated by insertion or deletion to a region in the genome using a homologous recombination vector.
Regarding claims 1, 10, and 11, Rudenko teaches genetically modified host cells that make cannabinoids or cannabinoid derivatives [Abstract]. Rudenko teaches that “Suitable prokaryote host cells include bacteria, e.g., eubacteria, such as Gram-negative or Gram-positive organisms, for example,… Vibrio natriegens…” [0087]. Rudenko teaches that the expression constructs “can be integrated into the chromosome of prokaryotic cells” [0066], and that the genomic integration can be performed “using well known techniques such as recombination”, cites a source teaching how to perform the well-known technique, and cites techniques to improve the efficiency of homologous recombination [0090]. Rudenko teaches that the host cell can use hexanoic acid to make CBGA, CBCA, CBDA and THCA [0005], and teaches the enzymes required [0006]. These enzymes include hexanoyl-CoA synthase which consumes hexanoic acid to produce hexanoyl-CoA, and geranyl-diphosphate:olivetolate geranyltransferase (GOT) [0006]. These enzymes produce cannabinoids and so are part of a cannabinoid biosynthetic pathway.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to generate the cannabinoid-producing genetically modified V. natriegens bacteria of Philippe by chromosomally integrating the heterologous enzymes using the homologous recombination protocol disclosed in Pfeifer and Rudenko and genetically modifying the prophage-cured V. natriegens strain of Pfeifer, because Pfeifer and Rudenko each teach that homologous recombination is a well-known technique usable in V. natriegens for making chromosomal insertions at the time of filing. Also, Pfeifer teaches many advantages to using their prophage-free strain of V. natriegens as the parental strain that is modified to generate a cannabinoid-producing genetically modified V. natriegens bacteria (improved robustness of the prophage-free variant toward DNA-damaging conditions, reduced cell lysis under hypo-osmotic conditions, and increased growth relative to the unmodified strain). The use of homologous recombination to make the insertions disclosed in Philippe could have been done with a reasonable expectation of success because Pfeifer demonstrates that homologous recombination can successfully be used in V. natriegens to make chromosomal insertions, and Rudenko independently suggests using the technique to insert cannabinoid biosynthesis genes into a bacterial chromosome.
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, the prior art (Philippe) discloses a product (a genetically modified V. natriegens for producing cannabinoids comprising specific insertions and mutations) but is silent about the method used to generate the specific insertions, and Pfeifer and Rudenko disclose homologous recombination as a well-known method for inserting nucleic acid into the chromosome of V. natriegens. Thus all elements (i.e. a genetically modified V. natriegens, the specific insertions and mutations to be made, and a method for performing those insertions and mutations) were known in the art. In addition, combining these elements yields a composition wherein each element merely performs the same function as it does separately; thus the results of the combination would be recognized as predictable to one of ordinary skill in the art.
Additionally, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to insert the gene into chromosome 1 of V. natriegens, because the art teaches that there are a finite number of options for insertion (plasmid, bacterial artificial chromosome, V. natriegens chromosome 1, or V. natriegens chromosome 2 as taught by Philippe and Pfeifer). Pfeifer and Rudenko each teach that homologous recombination is a well-known technique usable in V. natriegens for making chromosomal insertions, so the modification to any of the natural or artificial chromosomes could be made with a reasonable expectation of success. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success is obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp and if these options lead to the anticipated success, then the product was not of innovation but of ordinary skill and common sense. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
Applicant argues (Remarks pg. 6) that
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Applicant further argues (Remarks pg. 7) that insertion into chromosome 1 “was not an obvious choice from the cited prior art and also has been evidenced in the Declaration attached herewith. Pfeifer only describes prophage deletions from chromosome 1, not knock-ins of biosynthetic operons.”
Applicant further argues (Remarks pg. 7) “In a more profound manner, there is no explicit teaching suggesting that the chromosome 1 being an obvious choice for target, as in the present invention.”
Applicant further argues (Remarks pg. 7) “As a means, there is no explicit teaching suggesting the exact target being 'chromosome 1' for synergistic and stabilized production of cannabinoids, or its derivatives or its precursor derivatives, as claimed in the present invention.”
This argument has been carefully considered but is not persuasive. In response to applicant's argument that the references fail to show certain features of the invention (“site for insertion of multi-gene cannabinoid modules such as GOT, TKS, and OAC”, “synergistic production”), it is noted that the features upon which applicant relies (i.e., multi-gene modules, the presence of multiple different genes, synergistic production) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims do not require that multiple heterologous cannabinoid biosynthesis genes be present in the genetically modified V. natriegens (“encoding one or more polypeptides”). Also, there is no limitation in the claims requiring the different genes be inserted in the proposed multi-gene module rather than being individually inserted to the chromosome separately at different locations. So, the alleged improvements do not share a nexus with the claimed invention because the claim is not required to have the structural features of multi-gene modules that are argued to make chromosome 1 more advantageous than other insertion sites.
In response to applicant's arguments against the references individually (“While Philippe, Pfeifer, and Rudenko collectively describe V. natriegens engineering, none teaches or suggests targeted insertion of the claimed pathway genes into chromosome 1”), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection above did not argue that any of the individual references teach insertion of the claimed pathway genes into chromosome 1 of V. natriegens; this is not an anticipation rejection. Instead, the rejection argued that the art teaches that there are a finite number of options for the insertion location that can be chosen from with a reasonable expectation of success.
In KSR and other cases, the Supreme Court ruled that an explicit teaching or suggestion to combine is not always required, see MPEP 2141. A "motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill." Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018), see MPEP 2143.01. Additionally, in KSR, the Supreme Court ruled that an explicit teaching or suggestion to combine is not always required, see MPEP 2141. Also, in Ruiz v. A.B. Chance Co., 357 F.3d 1270, 69 USPQ2d 1686 (Fed. Cir. 2004), the court also rejected the notion that "an express written motivation to combine must appear in prior art references…." Id. at 1276, 69 USPQ2d at 1690, see MPEP 2143.01.
The reference to the evidence in the declaration is not persuasive because the declaration does not discuss the prior art cited here.
Applicant argues (Remarks pg. 7) that “The mere existence of two chromosomes does not render each an equally predictable locus for large, complex insertions.” “Because chromosome 1 contains essential functions, the skilled artisan would reasonably have expected stability problems and would have been deterred from placing a large foreign pathway there.”
This argument has been carefully considered but is not persuasive. Arguments relying on the alleged difficulty of inserting a large operon are not persuasive because inserting a large operon is not claimed. Applicant’s statements about the alleged drawbacks of performing insertions into chromosome 1 (containing essential functions) and their conclusions about one of ordinary skill in the art (would have expected stability problems, deterred from placing a large foreign pathway there, not an obvious choice) are only argument and not supported by objective evidence. See MPEP 716.01(c): “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.” (emphasis added). Contrary to applicant’s allegations, there is no evidence of record that one of ordinary skill in the art at the time of filing would consider homologous recombination to not occur with a reasonable expectation of success on chromosome 1 that is sufficient to overcome the evidence in Pfeifer demonstrating that homologous recombination can successfully be used in V. natriegens to make chromosomal insertions, and Rudenko’s independent suggestion to use the technique to insert cannabinoid biosynthesis genes into a bacterial chromosome as discussed in the rejection above. There is no evidence of record that one of ordinary skill in the art at the time of filing would expect stability problems or that one of ordinary skill in the art at the time of filing believes that chromosome 1 is a suboptimal choice compared to other known options.
Applicant argues (Remarks pg. 7) that “The Examiner's assertion that chromosome 1 was an "obvious target" is therefore an impermissible hindsight inference, inconsistent with In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998).”
Applicant further argues (Remarks pg. 7) that
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This argument has been carefully considered but is not persuasive. The relevance of In re Rouffet to the instant case is unclear. This case is not in the MPEP, and applicant has not explained any relationship between the instant case and Rouffet. The reference to In re Oetiker is also unclear; although it is cited in the MPEP, it is not cited in the context of hindsight. Therefore, the relevance of the Oetiker case to applicant’s argument is also unclear because applicant has not explained any relationship between the instant case and the cited case.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The rejection does not use improper hindsight relating to chromosome 1 because it relies only on what was within the level of ordinary skill at the time the claimed invention was made: that “the art teaches that there are a finite number of options for insertion (plasmid, bacterial artificial chromosome, V. natriegens chromosome 1, or V. natriegens chromosome 2 as taught by Philippe and Pfeifer). Pfeifer and Rudenko each teach that homologous recombination is a well-known technique usable in V. natriegens for making chromosomal insertions, so the modification to any of the natural or artificial chromosomes could be made with a reasonable expectation of success” (see rejection above). Applicant has not provided evidence disputing either the finite number of options or the reasonable expectation of success based on the art at the time of filing.
The rejection does not use improper hindsight relating to the use of Pfeifer’s prophage-free strain because it relies only on what was within the level of ordinary skill at the time the claimed invention was made: that “Pfeifer teaches many advantages to using their prophage-free strain of V. natriegens as the parental strain” (see rejection above) and also that KSR “discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill” (see rejection above). Applicant has not provided evidence disputing either Pfeifer’s disclosed benefits, that the rejection combined prior art elements according to known methods, or the reasonable expectation of success based on the art at the time of filing.
Applicant argues (Remarks pg. 7-8) that
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This argument has been carefully considered but is not persuasive. The data presented in the declaration will be discussed below in full, including a discussion of the alleged unexpected advantages of the claimed invention over the art. However, the argument that an insertion into chromosome 1 was not obvious to try because “the prior art neither identified chromosome 1 as a predictable solution nor suggested that such integration would yield superior cannabinoid production” is not persuasive. The “reasonable expectation of success” required by KSR does not require that there be a reasonable expectation of “superior cannabinoid production” because this feature is not claimed; it only requires that the bacteria be capable of the intended use of “wherein the genetically modified bacterium is engineered to consume hexanoic acid as a precursor to produce a cannabinoid, a cannabinoid derivative, or at least one cannabinoid precursor derivative.” In response to the predictability disclosed in the art, the rejection stated “Pfeifer and Rudenko each teach that homologous recombination is a well-known technique usable in V. natriegens for making chromosomal insertions, so the modification to any of the natural or artificial chromosomes could be made with a reasonable expectation of success.” The evidence in the declaration as summarized here does not show a lack of predictability because strains with integration into chromosome 1, chromosome 2, and the plasmid all produce some level of “a cannabinoid, a cannabinoid derivative, or at least one cannabinoid precursor derivative”.
Response to Declaration
The declaration under 37 CFR 1.132 filed 20 Jan 2026 is insufficient to overcome this rejection for reasons that are discussed in detail below. The declaration states:
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The method combines the DNA sequences from “five enzymes of a cannabinoid production pathway (see Figure 1)… utilizing preexisting genetic parts and methodology described in Stukenberg et al., 2021.” (Declaration pg. 2). “We proceeded to integrate the five transcription units from SEQUENCE 1 into the genome of V. natriegens by following the NT-CRISPR protocol outlined in Stukenberg et al., 2022” “The resulting strains, V. natriegens Adns::act-matB-ols-oac-nphB ("Adns::cOP") and V. natriegens APN96_18520::act-matB-ols-oac-nphB ("APN96_18520::cOP"), along with V. natriegens pMC2_cOP_Syn3_allMid (the plasmid containing act-matB-ols-oac-nphB) were cultivated” in conditions allowing fermentation and extracts from the culture media were analyzed for compounds of interest.
The figures are difficult to interpret because of image quality and because they use color-based labels to differentiate the strains but the declaration is submitted in black-and-white. The Figure 2 legend states: “Genomically integrated act, matB, ols, and oac are functional but produce significantly lower amounts of relevant compounds compared to the plasmid-based system. CBGA was not observed in any of the fermentations, precluding an assessment of nphB activity. Divarinic acid is a side product of Ols and Oac produced from natively generated butyryl-CoA and three units of malonyl-CoA. PDAL was only detectable with the plasmid-based strain.” The Figure 3 legend states: “Integration of the cannabinoid pathway into chromosome 1 (Adns::cOP; blue) results in a three-fold higher production of divarinic acid and more than four-fold higher production of olivetolic acid after 6h, compared to an integration into chromosome 2 (APN96_18520::00P; gray). After 24 h, the levels of divarinic acid and olivetolic acid are approximately equal in the two strains. Olivetol is produced in almost identical amounts in both strains”
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The evidence in the declaration has been carefully considered but not found persuasive. First, see MPEP 716.02(d): “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)”. The claims state: “the alterations comprise insertions of one or more heterologous nucleic acids encoding one or more polypeptides selected from a group consisting of geranylpyrophosphate:olivetolate geranyltransferase (GOT), tetraketide synthase (TKS), olivetolic acid cyclase (OAC)” (emphasis added). The declaration’s evidence using five different enzymes is not commensurate in scope with the claimed genus of modified V. natriegens bacteria currently claimed, so the evidence is insufficient to rebut the prima facie case of obviousness.
Second, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The declaration does not show that the strain with insertions into chromosome 1 is superior, it states that the plasmid strain is superior (“Genomically integrated act, matB, ols, and oac are functional but produce significantly lower amounts of relevant compounds compared to the plasmid-based system. … PDAL was only detectable with the plasmid-based strain.” Figure 2 legend). The declaration also does not argue that the difference between the different strains is unexpected; instead, it reasons that the difference is due to differences in copy number rather than an unexpected property: “This implies a reduced expression of the integrated transcription units, likely due to lower copy numbers compared to the plasmid-based system. … This effect may be explained by the generally lower copy number of chromosome 2 during rapid growth.” "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Third, the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). The evidence in the specification is based on a single experiment and that was not tested for statistical significance. The declaration also does not argue that the differences between chromosome 1 and chromosome 2 rise to the level of practical significance. Instead, the differences appear to be minor; Figure 2A appears to show that the difference between the two chromosome samples is negligible compared to the improvement in the plasmid strain.
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Therefore, the evidence in the declaration, and the argument in the Remarks that this evidence shows unexpected results, are not found persuasive to overcome the rejection of record.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMELIA NICOLE DICKENS whose telephone number is (571)272-0381. The examiner can normally be reached M-R 8:30-4:30, and every other F 8:30-4:30 (EDT/EST).
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/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645