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 .
Claim Status
The amendment of 08/21/2025 has been entered. Claims 3-4, 7-9, 13, 17-20, and 23-26 are pending in this US patent application. Claims 23-26 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to an invention that was nonelected by original presentation, there being no allowable generic or linking claim.
Claims 3-4, 6-9, 13, 15, and 17-20 are currently under examination and were examined on their merits.
Claim Interpretation
Claim 9 recites a composition “for treating a disorder causing gastrointestinal tract damage in human.” Claims 10-12 recite further limitations of the disorder recited in the preamble of claim 9. This statement in the preamble of claim 9 represents the intended use of the composition of claim 9. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP § 2111.02(II). In the instant case, claim 9 fully and intrinsically sets forth all of the limitations of the claimed invention. As such, the statements of intended use in the preamble of claim 9 and in claims 10-12 are of no significance to claim construction, and any prior art that reads on the structural limitations in the body of claim 9 will be interpreted to read on the entirety of claim 9 as well as on claims 10-12.
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.
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 3, 7, 9, 13, 18, and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over Chinese patent application CN 108753670 filed by Xu et al., published 11/06/2018 (cited on the IDS filed 04/21/2021), in view of Mays et al., Curr. Opin. Biotechnol. 53: 224-231 (2018; published 03/15/2018; cited on the IDS filed 05/23/2022), and Rajasree et al., Ind. J. Geo-Marine Sci. 43(5): 766-775 (2015), as evidenced by Wikipedia, https://en.wikipedia.org/wiki/M17_agar (accessed 05/22/2024), and Yan et al., Int. J. Clin. Exp. Med. 8(11): 20245-20253 (2015).
Please note that the page and paragraph numbers in this rejection refer to the translated copy of CN 108753670 attached to this Office action and not to the original Chinese-language document.
Xu teaches Lactococcus lactis recombinantly expressing VIP and cultured in M17 medium (see entire document, including page 3, paragraph 1; page 5, paragraph 2; cf. claims 9 and 13; please see above under Claim Interpretation for the Examiner’s interpretation of the statements of intended use in instant claim 9; the cells in the M17 medium could potentially be administered orally, and so this can be interpreted as an “oral dosage form” as recited in instant claim 13). In addition, Xu teaches that the VIP gene sequence ligated into the recombinant expression vector expressed in the Lactococcus lactis cells also includes the signal peptide sequence SPusp45 (page 4, paragraph 2). Xu teaches that the important ability of the probiotic bacteria used to express VIP is the ability to convert selenite into selenium nanoparticles (SeNPs; page 3, paragraphs 1-2).
Wikipedia teaches that M17 medium contains ascorbic acid (see entire document, including page 1, under “Typical composition”). As such, the composition comprising L. lactis cells recombinantly expressing VIP and M17 medium of Xu inherently contains ascorbic acid.
Yan teaches that ascorbic acid contributes to the reduction of oxidative stress and inflammatory response in colitis and exerts the potential to prevent and clinical treatment of inflammatory bowel disease (see entire document, including page 20245, abstract). As such, the ascorbic acid in the composition of Xu inherently constitutes a “therapeutic agent for treating a disorder causing gastrointestinal tract damage” as recited in instant claim 20.
However, Xu does not teach that the probiotic bacteria used to express the recombinant VIP vector are of the genus Lactobacillus or that the promoter used to drive VIP expression is a constitutive promoter as recited in the instant claims, or the location of the signal peptide sequence in the vector with respect to the promoter and VIP gene as recited in instant claims 7 and 18.
Mays teaches lactic acid bacteria have become the centerpiece of probiotics research (see entire document, including page 224, right column, paragraph 2). Lactic acid bacterial probiotics are now being directly engineered to produce conventional drugs, acting as living therapeutics (page 224, right column, paragraph 2). Gene expression in lactic acid bacteria can be driven by constitutive promoters, and a considerable number of constitutive promoters have been generated in Lactococcus lactis and Lactobacillus plantarum for synthetic biology and gene expression (page 225, left column, paragraph 1, to right column, paragraph 1).
Rajasree teaches that Lactobacillus plantarum reduces selenium ions to selenium nanoparticles (SeNPs) (see entire document, including page 766, abstract).
While Xu does not teach that the signal peptide sequence is located between the promoter and VIP gene in the microorganism as recited in instant claims 7 and 18, it would have been obvious to one of ordinary skill in the art to construct the vector of Xu in any manner in which the signal peptide SPusp45 is controlled by the promoter that also controls VIP expression, including in between the promoter and the VIP gene to allow for the signal peptide to be used as a marker for VIP expression. One of ordinary skill in the art would have a reasonable expectation that including the signal peptide SPusp45 sequence of Xu in the vector in between the promoter and the VIP gene would successfully allow for SPusp45 to be used as a marker for VIP expression.
While Xu does not teach that the probiotic bacteria used to express the recombinant VIP vector are of the genus Lactobacillus as recited in the instant claims, it would have been obvious to one of ordinary skill in the art to express the recombinant VIP vector in any probiotic bacterium that can produce SeNPs from selenium, such as Lactobacillus plantarum, which Mays teaches is a probiotic lactic acid bacterium that can be used for the expression of recombinant therapeutic genes and which Rajasree teaches can produce SeNPs from selenium ions. Similarly, while Xu does not teach that the promoter used to drive VIP expression is a constitutive promoter as recited in the instant claims, it would have been obvious to one of ordinary skill in the art to use a constitutive promoter to drive expression because Mays teaches that many constitutive promoters are available for Lactococcus lactis and Lactobacillus plantarum. Having the VIP gene expressed from a constitutive promoter would allow for expression even in the absence of the nisin inducer required by the vector of Xu. One of ordinary skill in the art would have a reasonable expectation that inserting a recombinant vector containing a VIP gene, as taught by Xu, controlled by a constitutive promoter into Lactobacillus plantarum, as taught by Mays, would successfully result in the production of a probiotic microorganism that expresses VIP in the absence of nisin and can convert selenium ions into SeNPs, as taught by Rajasree.
Therefore, claims 3, 7, 9, 13, 18, and 20 are rendered obvious by Xu in view of Mays and Rajasree, as evidenced by Wikipedia and Yan, and are rejected under 35 U.S.C. 103.
The Supreme Court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation…103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions……the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3-4, 7-9, 13, and 17-20 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11661445 in view of Chinese patent application CN 108753670 filed by Xu et al., published 11/06/2018 (cited on the IDS filed 04/21/2021). The cited claims of ‘445 recite a recombinant bacterium that can be of the genus Lactobacillus or Lactococcus that encodes a recombinant polynucleotide including a promoter that is equivalent to instant SEQ ID NO.: 10, a signal peptide that is equivalent to instant SEQ ID NO.: 11, and a foreign protein. The claims of ‘445 differ from the instant claims in that they do not recite that the foreign protein is VIP, as instantly recited. However, the teachings of Xu, as cited above, teach that VIP can be expressed recombinantly in probiotic bacteria, particularly Lactococcus lactis. As such, the instant claims are ‘rendered obvious’ by the claims of ‘445 in view of Xu and are rejected on the ground of nonstatutory double patenting.
Claims 3-4, 7-9, 13, and 17-20 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17/996436 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the recombinant microorganism of ‘436 is more narrow than the instantly recited organism. As such, the instant claims are ‘anticipated by’ the cited claims of ‘436 and are provisionally rejected on the ground of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3-4, 7-9, 13, and 17-20 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-18 of copending Application No. 18/301015 in view of Chinese patent application CN 108753670 filed by Xu et al., published 11/06/2018 (cited on the IDS filed 04/21/2021), in view of Mays et al., Curr. Opin. Biotechnol. 53: 224-231 (2018; published 03/15/2018; cited on the IDS filed 05/23/2022), and Rajasree et al., Ind. J. Geo-Marine Sci. 43(5): 766-775 (2015). The cited claims of ‘015 recite a recombinant cell that encodes a recombinant polynucleotide including a promoter that is equivalent to instant SEQ ID NO.: 10, a signal peptide that is equivalent to instant SEQ ID NO.: 11, and a foreign protein. The claims of ‘015 differ from the instant claims in that they do not recite that the foreign protein is VIP or that the host cell is a lactic acid bacterium, as instantly recited. However, these additional elements are known in the art from the teachings of Xu, Mays, and Rajasree, as discussed extensively above. As such, the instant claims are ‘rendered obvious’ by the claims of ‘015 in view of Xu, Mays, and Rajasree and are rejected on the ground of nonstatutory double patenting
This is a provisional nonstatutory double patenting rejection.
Claims Are Free of the Prior Art
In the interest of compact prosecution, the Examiner notes that claims 4 and 17 recite that the promoter consists of the sequence of SEQ ID NO.: 10, and claims 8 and 19 recite that the signal sequence encodes a peptide consisting of the sequence of SEQ ID NO.: 11. These sequences were first disclosed in KR 10-2017-0184819, filed 12/29/2017 (see corresponding US application 16/959058, now U.S. Patent No. 11661445). The Korean application was filed less than a year after the instant application and has multiple inventors in common with the instant case. As such, the instant claims reciting these sequences are free of the prior art.
Response to Arguments
Applicant has traversed the above rejection of the claims under 35 U.S.C. 103 as being unpatentable over Xu in view of Mays and Rajasree. Applicant states that VIP and sodium selenite are both toxic materials and that promoter strength is strain and context specific and can vary significantly between lactic acid bacteria. Applicant states that, accordingly, the inducible promoter of Xu cannot be replaced with the constitutive promoter of Mays because VIP is a toxic protein and the sodium selenite is also toxic. Applicant states that mass expression of the foreign VIP gene would impose an energetic and metabolic burden on the host cells, as would the presence of sodium selenite, as shown in the evidence of Chunlan Xu submitted with the response of 08/21/2025 (remarks, pages 5-7; see also pages 9-11 regarding metabolic burden). This argument has been fully considered but has not been found persuasive.
The Examiner notes that Xu specifically teaches the recombinant expression of VIP in bacteria for the purpose of producing a composition comprising probiotics, antibacterial peptides, and nano-selenium (Xu, page 3, paragraph 1; emphasis added). Xu is specifically making a recombinant probiotic bacterium that expresses VIP by Xu’s direct teaching. As such, the Examiner does not concur with Applicant’s unsupported assertion that constitutive VIP expression would be undesirable in a bacterium because Xu directly teaches that VIP can be expressed recombinantly in bacteria to produce compositions containing probiotic bacteria, antibacterial peptides, and nano-selenium. Regarding the energy/metabolic burden of protein expression that Applicant discusses, the Examiner reminds Applicant that all that is required for prima facie obviousness is a reasonable expectation of success, not an absolute certainty. It is certainly possible that combining Mays and Rajasree with Xu would result in an insurmountable metabolic burden on the cells. However, given that the expression of recombinant proteins in lactic acid bacteria is well understood in the art, the Examiner maintains that one of ordinary skill in the art would be motivated to produce the microorganism. The Examiner further notes that the claims are drawn only to a recombinant microorganism from one of the recited species containing a VIP gene operably linked to a constitutive promoter. There is no requirement that the microorganism be capable of anything, such as a specific amount of VIP expression or rate of microorganism growth.
Applicant states that Xu teaches away from using a constitutive promoter because Xu teaches a sequential process of producing selenium nanoparticles and VIP (remarks, pages 11-13). This argument has been fully considered but has not been found persuasive.
The Examiner notes that Xu in no place states that a constitutive promoter would be ineffective or inoperable. Teaching one method for performing a task does not somehow constitute a teaching away from all other methods of performing that task.
Applicant states that Mays teaches away from using a constitutive promoter for VIP because Mays teaches that inducible promoters are more useful and that the utility of a particular inducible promoter system is limited for toxic proteins because of leaky basal expression. Applicant further states that Mays “implies” that inducible promoters exhibiting leaky basal expression must be excluded, which Applicant states teaches away from the use of a constitutive promoter (remarks, pages 8, 11, and 13). This argument has been fully considered but has not been found persuasive.
The Examiner notes that Mays clearly teaches that constitutive promoters can be used. Even if Mays suggests that inducible promoters are more useful, a reference is prior art for all it contains and not just for preferred embodiments. See MPEP § 2123. In addition, the potentially limited utility for a particular inducible promoter system for toxic proteins as discussed by Mays is not relevant to the instant claims, which discusses a constitutive promoter system, not an inducible promoter system. Regardless of what Applicant thinks Mays “implies,” the Examiner must consider the actual text of Mays, which specifically and explicitly states that gene expression in lactic acid bacteria can be driven by constitutive promoters and that a considerable number of constitutive promoters have been generated in Lactococcus lactis and Lactobacillus plantarum for synthetic biology and gene expression. As such, Mays cannot be said to teach away from the use of constitutive promoters, a type of promoter that Mays explicitly teaches may be used.
Applicant states that one cannot assume interchangeability between Lactobacillus and Lactococcus because they belong to different genera, citing a Federal Circuit decision regarding the difference between bacteria and cyanobacteria (pages 11-12). This argument has been fully considered but has not been found persuasive because the expression of recombinant proteins in lactic acid bacteria, including Lactobacillus plantarum and Lactococcus lactis, is exceedingly well-understood in the art. See, for example, the Mays reference, which teaches that lactic acid bacteria have become the centerpiece of probiotics research (see entire document, including page 224, right column, paragraph 2) and that lactic acid bacterial probiotics are now being directly engineered to produce conventional drugs, acting as living therapeutics (page 224, right column, paragraph 2). The Examiner further notes that the difference between bacteria and cyanobacteria, organisms which are members of different phyla, is several orders of magnitude larger than the difference between Lactobacillus and Lactococcus, two lactic acid bacteria that are members of the same phylum, class, and order.
Applicant states that a separate incubation to biosynthesize selenium nanoparticles is required in the teachings of Xu and Rajasree and that it is not disclosed whether the biosynthesis of selenium nanoparticles in L. plantarum can proceed simultaneously with the expression and extracellular secretion of the recombinant VIP gene (remarks, pages 7-11). These arguments have been fully considered but have not been found persuasive.
The Examiner notes that the instant claims are drawn to a recombinant microorganism, not to any process of using said microorganism. As such, it does not matter whether the prior art teaches that the microorganism can express a particular recombinant protein at a particular point in its culture cycle or in the presence of a particular medium ingredient. All that is required for the claims is a recombinant Lactobacillus from one of the recited species that contains a heterologous VIP gene operably linked to a constitutive promoter, which would be obvious to one of ordinary skill in the art in light of the teachings of Xu, Mays, and Rajasree.
Applicant has traversed the above rejections of the claims on the ground of nonstatutory double patenting as being patentably indistinct from the claims of particular U.S. patents and patent applications in view of Xu. Applicant states that Xu is not relevant because it only discloses inducible expression of VIP in Lactococcus and not constitutive expression of VIP in Lactobacillus (remarks, pages 13-14). This argument has been fully considered but has not been found persuasive because the rejections also include the teachings of Mays and Rajasree, which do teach constitutive expression in Lactobacillus plantarum.
Therefore, the Examiner has maintained the rejections presented above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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, Sharmila Landau, can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Erin M. Bowers/Primary Examiner, Art Unit 1653 12/17/2025