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 .
DETAILED ACTION
Claims 1-3, 6-9, 11-12, and 14-15 are pending and under examination on their merits. Claims 4-5, 10, and 13 are cancelled.
The nonstatutory double patenting rejections over U.S. Patent No. 12,097,224 and 12,064458 are withdrawn in view of the terminal disclaimer filed on 12/11/2025.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claim 6 under 35 U.S.C. 101 on the grounds that the claimed subject matter is directed to human-made formulations and devices that have been structurally and functionally modified compared with any naturally occurring Rhodococcus ruber or its cell wall components, including through lyophilization, admixture with defined excipients in specific ratios, and incorporation into an external medical device. Applicant argues that these structural and functional modifications provide markedly different characteristics from any natural product (Arguments, paragraph 1 on page 8).
In response, these arguments are not persuasive because claim 6 recites a combination of the R. ruber cell wall skeleton with a pharmaceutically acceptable excipient that is not limited in structure. Therefore, the pharmaceutically acceptable excipient may be a liquid in which case the R. ruber cell wall skeleton is no longer lyophilized. Furthermore, the claim merely recites that the dressing is coated with the cell wall skeleton. In this case, the dressing merely acts as a container or holder for the natural product.
Applicant argues against the nonstatutory double patenting rejection over claims 1 and 5-10 of U.S. Patent No. 12,280,076 on the grounds that independent claims 1, 10, and 15 of the ‘076 patent are directed to combinations of R. ruber cell wall skeleton with stem cells in pharmaceutical compositions and methods, together with functional limitations relating to stem cells and/or promoting wound healing (Arguments, bottom paragraph on page 8). Applicant argues that the ‘076 patent does not claim the R. ruber strain per se, the cell wall skeleton per se, or the external medical device containing only the cell wall skeleton and excipients (Arguments, paragraph 1 on page 9). Applicant argues further that the ‘076 patent claims only combinations of the cell wall skeleton with the stem cells and specific therapeutic uses and that the claims do not recite the specific deposited strain CGMCC 17431 (Arguments, paragraph 1 on page 9).
In response, the strain CGMCC 17431 is recited in both claims 6 and 9 of ‘431. Furthermore, claim 5 recites a method of preparation of a lyophilized cell wall product from R. ruber. As explained in the Office action, it would have been obvious to the person of ordinary skill in the art to prepare the cell wall from R. ruber CGMCC 17431 by the method of claim 5 because claim 6 of ‘076 requires the cell wall product derived from Rhodococcus ruber CGMCC 17431. Thus, the obviousness-type nonstatutory double patenting rejection is proper because the instant application contains claims drawn to the same subject matter (a lyophilized R. ruber cell wall skeleton and the specific strain Rhodococcus ruber CGMCC 17431).
Claim Objections
Claim 6 is objected to because of the following informalities: An external medical device, comprising a dressing coated thereon with a composition which which comprises.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New Rejection Necessitated by Amendment) Claims 1-3, 6-9, 11-12 and 14-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “A lyophilized Rhodococcus ruber isolated from the Rhodococcus ruber deposited at the China General Microbiological Culture Collection Center (CGMCC) under Accession No. 17431.” The specification defines "Isolation" as the separation of the Rhodococcus ruber of the present disclosure from its original growth environment (specification, page 10, Detailed description of embodiments of the invention). In the microbiology arts, isolating bacteria typically refers to separating a specific microbe from a mixed sample. Under either interpretation, claim 1 is indefinite because the deposited bacteria is not a mixed sample of different strains of bacteria and it is not a growth environment. Applicant may consider amending to “A lyophilized Rhodococcus ruber deposited at the China General Microbiological Culture Collection Center (CGMCC) under Accession No. 17431.”
Claims 2-3, 6-9, 11-12 and 14-15 are rejected for depending from a rejected base claim and not rectifying the sources of indefiniteness discussed above.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The following rejections are necessitated by the amendment.
Claim 6 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
A flowchart has been established to determine subject matter eligibility under 35 U.S.C. 101. See MPEP 2106 part (III) and 2106.04 part (II)(A). The flowchart comprises answering: Step 1) Is the claim to a process, machine, manufacture or composition of matter? Step 2A Prong One) Does the claim recite an abstract idea, law of nature or natural phenomenon? Step 2A Prong Two) Does the claim recite additional elements that integrate the judicial exception into a practical application? Step 2B) Does the claim recite additional elements that amount to significantly more than the judicial exception? The claims are analyzed for eligibility in accordance with their broadest reasonable interpretation.
Claim 6 recites an external medical device, comprising a dressing coated thereon with a composition which comprises the Rhodococcus ruber cell wall skeleton of claim 2 and a pharmaceutically acceptable excipient. Claim 6 depends from claim 2, which recites a lyophilized cell wall skeleton derived from the isolated Rhodococcus ruber of claim 1. Claim 1 is drawn to a Rhodococcus ruber deposited under CGMCC Accession No. 17431. Claim 6 is drawn to both an article of manufacture (a dressing) and a composition of matter (Rhodococcus ruber cell wall skeleton). Both article of manufacture and composition of matter are statutory categories of invention (Step 1: Yes). Claim 6 recites the judicial exception of a Rhodococcus ruber CGMCC 17431 cell wall skeleton, which is a product of nature (Step 2A Prong One: Yes). The specification does not disclose the source of the isolate (see page 15, line 1 of Example 1). SEQ ID NO: 1 is the nucleotide sequence encoding the 16S ribosomal RNA of CGMCC Accession No. 17431. This sequence is 99.78% identical to Rhodococcus ruber strain DSM43338T (OA Appendix A of the Non-Final Action mailed on 9/23/2025). DSM43338T is naturally occurring in aquatic samples, soil samples, animal samples, and plant samples (see BacDrive, 2024 website; “Isolation, sampling, and environmental information;” cited in the Non-Final Action mailed on 9/23/2025). Therefore, Rhodococcus ruber CGMCC Accession No. 17431 does not have markedly different characteristics than a product of nature. Although claim 6 recites that the cell wall skeleton is lyophilized, because the pharmaceutically acceptable excipient is not limited, the broadest reasonable interpretation of excipient includes liquid excipients (e.g. castor oil, see specification page 13, paragraph 1). The combination of a lyophilized cell wall with an excipient such as castor oil wets the cell wall, so it is no longer lyophilized. Thus, the cell wall does not have markedly different characteristics than a product of nature.
Claim 6 does not integrate the judicial exception into a practical application (Step 2A Prong Two: No). Claim 6 recites a combination: a R. ruber cell wall skeleton and an excipient and a dressing. However, these are generic limitations that do not materially limit the product of nature (R. ruber cell wall skeleton) because the claim does not require the dressing to be structurally connected to or structurally modified with the cell wall skeleton. Note that “coated thereon” is equivalent to putting the R. ruber cell wall skeleton on top of the dressing. Thus, the recited external medical device (a dressing) serves as a holder or container for the R. ruber cell wall skeleton. They are equivalent to adding the words “apply it” to the judicial exception. Furthermore, pharmaceutical excipients as well as a dressing are all well-understood, routine, and conventional (see, for example, Wang et al. (Journal of international medical research 46.6 (2018): 2398-2409; cited in the Non-Final Action mailed on 9/23/2025; Abstract, which describes gauze soaked in Vaseline and Rhodococcus ruber cell wall skeleton). Therefore, claim 6 is ineligible under 35 U.S.C. 101 (Step 2A Prong Two and Steps 2B: No).
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.
The following rejections are necessitated by the amendment.
Claims 1-2, 7-9, 11-12, and 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5-10 of U.S. Patent No. 12,280,076 (‘076). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-2, 7-9, 11-12, and 14-15 are obvious over claims 1 and 5-10 of ‘076.
Claim 1 of ‘076 recites “A method of regulating mesenchymal stem cells comprising exposing the stem cells to a product derived from Rhodococcus ruber cell wall; wherein the ratio of the number of stem cells to the product derived from Rhodococcus ruber cell wall is 1 to 100 stem cells per 1 ng of the product derived from Rhodococcus ruber cell wall.”
Claim 5 of ‘076 recites a method for obtaining a Rhodococcus ruber cell wall, which include in step 4) removing water from the product derived from Rhodococcus ruber cell wall, preferably lyophilizing the product derived from Rhodococcus ruber cell wall.
Claim 6 of ‘076, which depends from claim 1 of ‘076, limits the Rhodococcus ruber to CGMCC No. 17431.
Claim 7 of ‘076 recites a cell culture medium comprising a product derived from Rhodococcus ruber cell wall and a mesenchymal stem cell, wherein the product derived from Rhodococcus ruber cell wall is Rhodococcus ruber cell wall or a component thereof.
Claim 8 of ‘076 recites the steps of the method of obtaining the Rhodococcus ruber cell wall, which include in step 4) removing water from the product derived from Rhodococcus ruber cell wall, preferably lyophilizing the product derived from Rhodococcus ruber cell wall.
Claim 9 of ‘076 recites that the Rhodococcus ruber is CGMCC No. 17431.
Claim 10 of ‘076 recites “A method for promoting wound healing, comprising exposing a subject having a wound to a therapeutically effective amount of stem cells and a product derived from Rhodococcus ruber cell wall, wherein the stem cells are selected from the group consisting of mesenchymal stem cells and the ratio of the number of stem cells to the product derived from Rhodococcus ruber cell wall is 1 to 100 stem cells per 1 ng of the product derived from Rhodococcus ruber cell wall.”
Regarding instant claim 7, claim 5 of ‘076 recites the exact same method steps as the instant claim 7 except that the Rhodococcus ruber is not limited to CGMCC No. 17431 and claim 5 of ‘076 does not recite that the average particle size of the disruption is 10 nm to 1000 nm; wherein the aliquoting is into containers selected from the group consisting of: vial, tube, package, bag, plate, ampoule, injection device, aluminum film packaging, dressing and capsule.
However, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to isolate the cell wall of Rhodococcus ruber CGMCC No. 17431 per the method of claim 5 of ‘076 given that CGMCC No. 17431 is required to practice the method of claim 6 of ‘076. The person of ordinary skill in the art would have had a reasonable expectation of success in specifically using Rhodococcus ruber CGMCC No. 17431 in the method of claim 5 of ‘076.
It would have been further obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the step of disrupting to achieve the desired particle size. The person of ordinary skill in the art would have had a reasonable expectation of success given that particle size is a results-effective variable based upon the severity of the conditions used for disruption
Regarding the containers for aliquoting, it would have been obvious to the person of ordinary skill in the art to aliquot the product derived from the Rhodococcus ruber cell wall (the cell wall skeleton) into a dressing for its intended use in treating wounds (see claim 10 of ‘076). The person of ordinary skill in the art would have had a reasonable expectation of success in aliquoting the product into a dressing.
Instant claims 1-2 are unpatentable over claims 5-6 of ‘076 because the product derived from claim 5 of ‘076 is necessarily a cell wall skeleton because the active steps of the method are the same. The R. ruber product is lyophilized in step 4). Furthermore, it would have been obvious to the person of ordinary skill in the art to derive the lyophilized cell wall skeleton from Rhodococcus ruber CGMCC No. 17431 because CGMCC No. 17431 is required to practice the method of claim 6 of ‘076. Therefore, the lyophilized, isolated strain (instant claim 1) and the lyophilized, isolated cell wall skeleton (instant claim 2) are both obvious over claims 5-6 of ‘076.
The instant claim 7 is obvious over claim 5 of ‘076 given that performing the method of claim 5 of ‘076 with Rhodococcus ruber CGMCC No. 17431 necessarily produces a lyophilized Rhodococcus ruber cell wall skeleton because the active steps of the method of claim 5 of ‘076 and that of instant claim 7 are the same.
Regarding instant claims 8-9, claim 5 of ‘076 does not recite that the average particle size is 10 nm to 800 nm (claim 8) or 10 nm to 500 nm (claim 9).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the step of disrupting to achieve the desired particle size. The person of ordinary skill in the art would have had a reasonable expectation of success given that particle size is a results-effective variable based upon the severity of the conditions used for disruption.
Instant claims 11-12 and 14-15 are obvious over claim 5 of ‘076 because in one embodiment, each of the optional steps of claim 5 of ‘076 is performed.
Claim 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5-10 of U.S. Patent No. 12,280,076 (‘076) in view of Inamura et al. (The Journal of Antibiotics 37.3 (1984): 244-252; cited in the Non-Final Action mailed on 9/23/2025).
See discussion of claims 1 and 5-10 of ‘076 above, which is incorporated into this rejection as well.
Regarding instant claim 5, claims 1 and 5-10 of ‘076 do not recite that the lyophilized R. ruber cell wall skeleton is in a lyophilized powder formulation with an excipient.
Inamura teaches a lyophilized pharmaceutical formulation comprising Nocardia rubra (Rhodococcus ruber) cell wall skeleton with the excipients squalene, polysorbate 80, and mannitol, that is reconstituted before use (paragraph bridging pages 244-245).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to lyophilize the Rhodococcus ruber CGMCC 17431 cell wall skeleton of claims 1 and 5-10 of ‘076 with an excipient such as mannitol per the teaching of Inamura in order to store the composition prior to its intended use. The person of ordinary skill in the art would have had a reasonable expectation of success in the lyophilization of Rhodococcus ruber cell wall skeleton CGMCC 17431 with an excipient.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 10-12 of U.S. Patent No. 12,280,076 (‘076) in view of Wang et al. (Journal of international medical research 46.6 (2018): 2398-2409; cited in the Non-Final Action mailed on 9/23/2025).
Claim 5 of ‘076 is drawn to a method comprising obtaining a product derived from R. ruber cell wall and lyophilizing the product (step 4).
Claim 10 of ‘076 recites a method for promoting wound healing comprising exposing a subject having a wound to a therapeutically effective amount of stem cells and a product derived from Rhodococcus ruber cell wall, wherein the stem cells are selected from the group consisting of mesenchymal stem cells and the ratio of the number of stem cells to the product derived from Rhodococcus ruber cell wall is 1 to 100 stem cells per 1 ng of the product derived from Rhodococcus ruber cell wall.
Claim 12 of ‘076 recites the R. ruber is CGMCC 17431.
Regarding instant claim 6, claims 5 and 10-12 of ‘076 do not recite an external medical device comprising a dressing coated with a lyophilized Rhodococcus ruber CGMCC 17431 cell wall skeleton and a pharmaceutically acceptable excipient. Excipient is interpreted according to its plain meaning as an inactive substance that serves as the vehicle or medium for a drug or other active substance.
Wang teaches a Vaseline gauze soaked in Nocardia rubra (synonym for Rhodococcus ruber) cell wall skeleton (Abstract Objective and Abstract Methods). In other words, Wang teaches an external medical device (the gauze, which is a wound dressing) comprising a pharmaceutically acceptable excipient (Vaseline) and Nocardia rubra cell wall skeleton.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the lyophilized cell wall skeleton of CGMCC 17431 per the method of claim 5 of ‘076 because the product derived from R. ruber CGMCC 17431 cell wall is required by the method of claim 12 of ‘076. It would have been further obvious to formulate the lyophilized Rhodococcus ruber CGMCC 17431 cell wall skeleton of claim 5 of ‘076 with Vaseline on gauze (dressing) such that the pharmaceutical composition could be administered as an external medical device to promote wound healing (claims 10 and 12 of ‘076). The person of ordinary skill in the art would have had a reasonable expectation of success in these modifications.
Examiner’s Comment
Rhodococcus ruber CGMCC 17431 has been deposited and a statement of public availability of the deposited strain is included within the instant specification. See bottom paragraph on page 1 of the specification “Biological Deposit of Rhodococcus ruber Accession No. 17431.”
No prior art rejection is made of claim 1 and its dependents, which require R. ruber CGMCC No. 17431, which is not taught by the prior art. With respect to the cell wall skeleton of CGMCC No. 17431 (relevant to claims 2-6 and 10), the prior art does not teach whether there is strain-level variation in the cell wall skeleton of Rhodococcus ruber (previously classified as Nocardia rubra). However, a closely related family of Nocardia bacteria has strain-level differences in the mycolic acid composition in the cell wall: see Table 2 on page 119 of Nishiuchi et al. (Journal of microbiological methods 37.2 (1999): 111-122; cited in the Non-Final Action mailed on 9/23/2025) and the phylogenetic tree on page 380 of Gürtler et al. (FEMS Microbiology Reviews 28.3 (2004): 377-403; cited in the Non-Final Action mailed on 9/23/2025), which demonstrates the close relationship between Nocardia and Rhodococcus species. Therefore, the person of ordinary skill in the art would have predicted based on the state of the art that Rhodococcus ruber also demonstrates strain-level differences in the composition of the cell wall skeleton.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657