DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on 12/18/25 was filed and entered. The submission is in compliance with the provisions of 37 CFR 1.97 and has been considered by the Examiner.
Declaration under 37 C.F.R. 1.132
3. The declaration under 37 CFR 1.132 filed 12/18/25 is insufficient to overcome the rejection of (A) claims 1-2, 84-86, and 90-91 under 35 U.S.C. 102(a)(1) as being anticipated by Miller et al. 2005 (US 2005/0287625); (B) claims 1-2, 84-86, 88, and 90-91 under 35 U.S.C. 103 as being unpatentable over Miller et al. 2005 (US 2005/0287625) in view of Vuilleumier et al. 2009 (PLoS ONE; 4(5): e5584); or (C) claims 1-2, 84-88, and 90-92 under 35 U.S.C. 103 as being unpatentable over Miller et al. 2005 (US 2005/0287625) in view of Chubiz et al. 2013 (BMC Research Notes 6:183); as set forth in the last Office action because it is not commensurate in scope with the requirements for the rejection(s) and thus, when all of the evidence is considered, the totality of the rebuttal evidence against anticipation (and by extension) non-obviousness fails to outweigh the evidence of record for the anticipation rejection (see Response to Arguments, below).
Claim Status
4. The amendment, filed 12/18/25, has been entered. Claims 1-2, 84-88, and 90-92 are pending and under examination. Claims 3-83 and 89 are cancelled. Claims 85-87 are amended.
Withdrawal of Objections/Rejections
5. The following are withdrawn from the Office Action, filed 06/18/25:
The rejection of claim 89 under 35 U.S.C. 112(a) as failing to comply with the written description requirement, found on page 3 at paragraph 7, is moot in light of Applicant’s cancellation thereof.
The rejection of claims 85, 87, and 89 under 35 U.S.C. 112(b) as being indefinite, found on page 4 at paragraph 9, is withdrawn in light of Applicant’s amendments thereto or cancellation thereof.
Maintained Rejection: Claim Rejections - 35 USC § 102
6. 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.
7. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
8. Claims 1-2, 84-86, and 90-91 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miller et al. 2005 (US 2005/0287625).
Miller discloses methods of making transconjugant methylotrophic bacteria via conjugation comprising the use of a mobilizable plasmid having an origin of replication (e.g. ortT); and a donor and a recipient cell (abstract; [0150-0151; 0199-0200]; meeting limitations found in instant claims 1 and 84). Miller discloses the use of vectors with selectable markers, including kanamycin resistance markers, to detect and identify (i.e. selected and/or screened) successful transfers between donors and recipients (e.g. [0117; 0128; 0183; 0189-92; 0266-0267; 0310]; and Examples 6 & 7; meeting limitations found in instant claims 1, 2, and 85-86). Miller teaches the use of screening markers for assaying thousands of individual integration events in parallel (i.e. markers in both donor and recipient cells; e.g. see [0207]). Miller discloses methylotrophic bacteria having mutations in the carotenoid biosynthesis pathway (e.g. [0078-80; 0115]; meeting limitations found in instant claim 90). Miller discloses mutants with the crt cluster (including crtI) are disrupted (e.g. [0098; 0103; 0153-0154; 0158]; meeting limitations found in instant claim 91). Miller discloses methylotrophic bacteria suitable in the invention include Methylobacterium ([0164]; meeting limitations found in claim 1). Miller discloses that invention solved known problems with expression systems by, in part, identifying a region of the methylotroph genome where a coding region can be introduced for high expression including using conjugation and mobilizable plasmids carrying necessary genes and/or nucleotide sequences and/or identifying markers (e.g. [0013, 0150-0151, 0199-0204, 0207]). Miller discloses that the plasmid maybe be derived from any source (e.g. see [0151]). Although Miller discloses the use of helper cells having helper plasmids, Miller does not require the helper cell (i.e. teaches triparental conjugation as an alternative); including explicitly stating “…In some cases, only a donor and recipient are required for conjugation” (emphasis added; e.g. see [0150, 0199-0201]; meeting broadest reasonable interpretation of claim 1).
Therefore, Miller anticipates the invention as claimed.
Applicant’s Arguments and Response to Arguments
9. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the statement that “…the Miller reference fails to disclose bi-parental transfer” (see Remarks, page 5) and the argument that Miller is limited to tri-parental conjugation (see Remarks, page 6 citing [0291-0292]); the Office disagrees and notes, inter alia, Miller at paragraph 200, which explicitly states
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Thus, it remains the Office’s position that Miller unequivocally envisioned conjugation to include both with (i.e. tri-parental, see [0201]) and without (i.e. bi-parental conjugation; see “…only a donor and recipient are required” in [0200]; emphasis added) helper plasmids. Thus, this argument is not persuasive because it is not an accurate reflection of the art of record (e.g. see consecutive paragraphs with a “1.” followed “2. Alternatively…”).
With regards to the Declaration, it is noted that Dr. Breakfield (i.e. the inventor) states Miller provides no experimental data demonstrating two-parent conjugation because Examples 1-4 contain no bi-parental conjugation experiments, no transfer frequencies, and no donor-recipient mating procedures; and no tables, figures, selectable markers, counterselection conditions, or mating results that would constitute a bi-parental transfer (see Declaration at paragraph 5). However, Applicant is reminded that (A) patents are relevant for all they contain (e.g. see instant [0199-0201] and MPEP 2123); and that (B) working examples are not required by the Applicant and/or in the prior art (see MPEP 2164.02); and (C) MPEP 2121 states that 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 provide facts rebutting the presumption of operability in re Sasse 629 F.2d 675,207 USPQ 107 (CCPA 1980); see also MPEP § 716.07. Thus, this argument is not persuasive (or germane) because the lack of experimental data by Miller is not required and does not negate the teaching by Miller that conjugation included situations in which only a donor and recipient (i.e. bi-parental) would be required, as set forth above.
Therefore, all of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Maintained Rejection: Claim Rejections - 35 USC § 103
10. 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.
11. 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.
12. 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.
13. Claims 1-2, 84-86, 88, and 90-91 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. 2005 (US 2005/0287625) in view of Vuilleumier et al. 2009 (PLoS ONE; 4(5): e5584).
The teachings of Miller are set forth above. Therefore, the difference between the prior art and the invention is that even though Miller explicitly teaches that the plasmid may be derived from any source, Miller is silent as to wherein the plasmid is a native Methylobacterium plasmid, as claimed in dependent claim 88.
However, Vuilleumier discloses the genomes of Methylobacterium are known and include multiple useful plasmids which provide a platform for intra- and inter-species genomic comparisons (see abstract; page 2, right column; Table 1). Vuilleumier discloses Methylobacterium extorquens has served as a model organism for over four decades and data for its genome has been available since 2003 (see page 2, left column). Vuilleumier discloses horizontal gene transfer represents key mechanisms of Methylobacterium evolution (e.g. page, conclusions).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the methods of Miller by using the teachings of Vuilleumier, including for the use of a native plasmid, thereby arriving at the claimed invention, to ensure compatibility between the Methylobacterium donor and recipient cells by relying on the known capacity for horizontal gene transfer, as taught by Vuilleumier. Thus, each element is taught in the prior art and the combination has a beneficial result; however, the combination amounts to no more than a predictable use of prior art elements according to their established functions. The person of ordinary skill in the art would have been motivated to make the modification, with a reasonable expectation of success, because Miller already taught that the plasmid could be derived from any source and the Methylobacterium genome, including useful plasmids, was already known and already used as a model organism, as taught by Vuilleumier. Therefore, the combination leads to expected results because each element performs the same function as it does individually.
Additionally, 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, all elements (i.e. methods for making Methylobacterium transconjugants via conjugation of plasmids; and native plasmids of Methylobacterium prone to horizontal gene transfer) were known in the art. In addition, combining these elements yields a method 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.
Consequently, it would have been obvious to a person of ordinary skill in the art to combine these prior art elements according to a known method to yield predictable results. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Applicant’s Arguments and Response to Arguments
14. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the argument that Vuilleumier does not remedy the deficiencies noted for the 102(a)(1) rejection over Miller (see Remarks, pages 6-7 bridging section); it is noted that the Office does not deem Miller deficient (see above). Thus, this argument is not persuasive because it does not address the combination of references with regards to limitations found in dependent claim 88.
Therefore, all of Applicant' s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Maintained Rejection: Claim Rejections - 35 USC § 103
15. Claims 1-2, 84-88, and 90-92 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. 2005 (US 2005/0287625) in view of Chubiz et al. 2013 (BMC Research Notes 6:183).
The teachings of Miller are outlined above. Therefore, the difference between the prior art and the invention is wherein the mobilizable plasmid is a native Methylobacterium plasmid (dependent claim 88); and/or wherein the origin of replication is an RK2 origin of replication (dependent claim 92); and/or wherein the selectable marker encodes a fluorescent protein (dependent claim 87).
However, Chubiz discloses similar expression vectors for use in substantially the same methylotrophs, including Methylobacterium, which has been recognized as a model organism for over 50 years (see abstract; introduction). Chubiz discloses plasmids having RK2 transfer origins and encoding fluorescent proteins (see page 7, methods; and Figure 1). Chubiz discloses broad-host-range extensible genetic tools is desirable for prokaryotes other than E. coli and Pseudomonas (see introduction). Chubiz discloses the expression system expands the genetic toolkit available to research working with Methylobacterium and provide(s) a significant improvement and will easily work in concert within a single strain to allow complex genetic engineering in a wider range of bacteria (e.g. page 6, conclusions). Chubiz discloses a variety of plasmids with similar backbones (e.g. page 4, right column; and page 6, left column).
With regards to wherein the mobilizable plasmid is a native Methylobacterium plasmid, the plasmids of Chubiz appear to be native to Methylobacterium; however, since the Office does not have the facilities for examining and comparing Applicant’s plasmid with that of the prior art reference, the burden is now upon the Applicant to show an unobvious distinction between the material structural and functional characteristics of the claimed plasmid with that of the prior art; emphasis added; See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594. Further, MPEP 2112.01 states that “When the PTO shows a sound basis for believing that the inventions of the Applicant and the prior art are the same, the Applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the teachings of Miller, by using the plasmid(s) of Chubiz, thereby arriving at the claimed invention, in order to expand the genetic toolkit available for Methylobacterium, as taught by Chubiz. Therefore, each and every element is taught in the prior art and the combination has a beneficial result; however, the combination amounts to no more than a predictable use of prior art elements according to their established functions. The person of ordinary skill in the art would have been motivated to make the modification, with a reasonable expectation of success, because Miller had already taught Methylobacterium as a desirable methanotroph to modify via conjugation, and Miller had already taught that the plasmid may be derived from any source, and Chubiz had already demonstrated similar modifications for similar plasmids in Methylobacterium, as set forth above. Therefore, the combination leads to expected results because each element performs the same function as it does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain 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, Miller teaches a method and product that only differs from the claimed invention by the substitution of a single component (i.e. substitution of the plasmid used in the method); the substituted element (i.e. native Methylobacterium plasmids with RK2 origin of replication and encoding fluorescent, screenable, protein markers) was already known and already used as a vector, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of substituting one plasmid for another with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results).
Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Applicant’s Arguments and Response to Arguments
16. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the argument that Chubiz does not remedy the deficiencies noted for the 102(a)(1) rejection against Miller (see Remarks, page 7); it is noted that the Office does not deem Miller deficient (see above). Thus, this argument is not persuasive because it does not address the combination of references with regards to limitations found in dependent claim 87, 88, or 92.
Therefore, all of Applicant' s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Pertinent Art
17. The following prior art, made of record and not relied upon, is still considered pertinent to Applicant’s disclosure: Chistoserdova et al. 2004 (Multiple formate dehydrogenase enzymes in the facultative methylotroph Methylobacterium extorquens AM1 are dispensable for growth on Methanol; Journal of Bacteriology 186(1):22-28; of record) teaches both biparental and triparental conjugation in Methylobacterium species was already known (e.g. see page 23, left column). Therefore, Chistoserdova teaches that one of ordinary skill in the art (circa 2004) would recognized that Miller does not require the helper cells and thereby envisioned both biparental and triparental conjugation.
Conclusion
18. No claims are allowed.
19. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
20. 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.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY MAILLE LYONS whose telephone number is (571)272-2966. The examiner can normally be reached on Monday-Friday 8 am to 5 pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http: //www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Kolker can be reached on (571)-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY MAILLE LYONS/Examiner, Art Unit 1645
January 26, 2026