DETAILED ACTION
Claims 1-3 and 7-15 are pending. Of these, claims 9-15 are withdrawn as directed to a nonelected invention. Therefore, claims 1-3 and 7-8 are under consideration on the merits.
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 .
Status of the Rejections
The 103 rejection is revised in view of the amendment.
The double patenting rejection is maintained.
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 1-3 and 7-8 are rejected under 35 U.S.C. 103 as unpatentable over Duan et al. (Biochemical and Biophysical Research Communications 506 (2018) 619-625; of record in IDS) in view of Kojima et al. (Biomaterials 33 (2012) 4508-4514) and Jhunjhunwala et al. (J Control Release 2009 February 10; 133(3): 191-197).
As to claims 1-3 and 7-8, Duan discloses that administration of a composition of mesenchymal stem cells suppresses immune rejection in various transplantation animal models via regulation of Tcells, and further discloses that co-administering 0.1 mg/kg/day rapamycin in combination with 1X 106 of the mesenchymal stem cells resulted in enhanced delaying of graft rejection after transplantation of pancreatic islet cells in a mouse model, leading to enhanced islet function as measured by better glycemic control and increased insulin secretion upon glucose challenge (Abstract, Sections 2 and 3.1-3.2, and first paragraph of Section 4).
As to claims 1-3 and 7-8, Duan does not further expressly disclose a composition comprising spheroids comprising the mesenchymal stem cells and rapamycin, and wherein the rapamycin is in the form of microparticles as recited by claims 1 and 8, wherein the microparticles are present in the amount of claim 2 and comprise a polymer of claim 2 that is the elected species, i.e., PLGA of claim 3, wherein the amounts of the mesenchymal stem cells and rapamycin are as recited by claim 1 or that PD-L1 expression is increased (claim 1) by the rapamycin microparticle leading to suppression of immune rejection of a transplant (claim 6).
Kojima discloses that, compared to monolayer cell cultures, a composition comprising multicellular aggregates (i.e., spheroids) along with microspheres have superior properties, because aggregate formation enhances cell viability and function (first paragraph of the introduction on page 4508). Kojima demonstrates the formation of the aggregates through a method comprising mixing polystyrene microspheres with animal cells in a solution comprising methylcellulose, resulting in aggregation (Abstract and sections 2.1-2.5).
Jhunjihunwala discloses that degradable microparticles can protect and release drugs over extended periods (Abstract), and further teaches that dendritic cells treated with rapamycin encapsulated into PLGA microparticles had significantly reduced ability to activate T Cells relative to dendritic cells treated with non-encapsulated rapamycin (Abstract, 1st paragraph of Introduction, 2nd paragraph of page 7). Jhunijihunwala concludes that PLGA-microencapsulated rapamycin may be useful in treating transplant rejection (last paragraph of page 8). PLGA was used in the amount of 200mg and rapamycin in the amount of 100 microliters of a 10 mg/ml solution, or 1 mg, resulting in 0,5 parts by weight rapamycin and 99.5 parts by weight of the PLGA, which is within the ranges of claim 2 (paragraph bridging pages 2-3).
As to claims 1-3 and 7-8, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the teachings of Duan by microencapsulating the rapamycin with PLGA followed by forming hybrid spheroids comprising the mesenchymal stem cells and the rapamycin microparticles to form a composition for suppressing immune rejection, because Jhunjihunwala teaches that PLGA microparticles advantageously can protect and release drugs over extended periods and that rapamycin encapsulated into PLGA microparticles significantly reduced the ability of immune cells to activate T Cells which is useful in suppressing immune rejection after a transplant, and Kojima discloses that a cell composition comprising multicellular aggregates and microspheres has superior properties relative to unaggregated monolayer cells, because aggregate formation enhances cell viability and function, such that the skilled artisan reasonably would have expected that microencapsulating the rapamycin with PLGA would help to protect and release the rapamycin over time so as to enhance immune suppression after a transplant, and further that forming hybrid spheroids comprising the mesenchymal stem cells and the rapamycin microparticles would improve the function of the mesenchymal stem cells upon transplant by promoting aggregation of the cells. Additionally, since Duan and Jhunjihunwala teach the use of specific amounts of mesenchymal stem cells and rapamycin, apportioning said stem cells and rapamycin to the spheroids in amounts within the ranges of claim 1 would have been within the purview of one of ordinary skill in the art. There would have been a reasonable expectation of success in selecting a lower amount of mesenchymal stem cells than taught by Duan in order to arrive at the amount recited by claim 1 because the mesenchymal stem cells are being used by Duan for the same purpose as the claimed invention (i.e., to suppress immune rejection after transplantation of pancreatic islet cells) and further because the skilled artisan would have expected that the method of the prior art as combined above (involving, unlike the Duan method, the use of the stem cells in the form of spheroid aggregates containing the rapamycin) would require fewer mesenchymal stem cells to obtain the same therapeutic effect in light of Kojima’s teaching that the use of cellular aggregates enhances cell viability and function and Jhunijihunwala’s teaching that PLGA-microencapsulated rapamycin also treats transplant rejection, such that the use of a spheroid combining an aggregate of the stem cells with rapamycin that is microencapsulated reasonably would be expected to have greater potency. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 2, it further would have been prima facie obvious to select amounts of the rapamycin and polymer in the rapamycin particles to be within the claimed ranges, because Jhunijihunwala discloses that rapamycin particles having such proportions are suitable for use in delivering rapamycin for the purpose of suppressing immune rejection of a transplant.
The resulting composition will suppress immune rejection of a transplant due to an increase in PD-L1 expression as recited by claim 1 caused by the rapamycin microparticles wherein the transplant is of any one or more of the cells recited by claim 7 such as stem cells based upon the evidence of record because it comprises the same ingredients in the same spheroid structure in the same amounts as discussed above. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01.
Response to Applicant’s Arguments
Applicant argues that the results obtained by the claimed invention are dramatically higher than achieved by the Duan method, with many mice maintaining long term graft survival well beyond 50 days, and that such outcomes are completely unexpected in the field of islet transplantation where even incremental improvements in survival are difficult to achieve. Applicant asserts that the claimed combination therapy comprising MSC/rapamycin-microparticle spheroids results in a synergistic effect not predictable from the cited references.
In response, whether 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) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). MPEP 70602(d).
Here, the working examples tested spheroids comprising rapamycin encapsulated into PLGA microspheres (paragraph 42 as published). The claims, however, are not so limited. Claim 1 only recites “rapamycin microparticles,” with no requirement that the rapamycin is microencapsulated. Therefore, the claims are not commensurate in scope with the spheroid composition of the working examples. The lack of any requirement in the claims that the rapamycin is microencapsulated by PLGA is especially significant in light of Jhunjihunwala’s teaching that PLGA microparticles encapsulating rapamycin protects and releases the drug over extended periods, and is significantly superior to the use of non-encapsulated rapamycin when treating transplant rejection as discussed in the rejection. Therefore, the skilled artisan reading Jhunjihunwala reasonably would have expected that the fact that the rapamycin of the inventive composition was PLGA micro-encapsulated may have played a significant role in the superior results of the claimed composition, such that the superior results could not reasonably be extrapolated over the full scope of the claims which do not require such microencapsulation, based upon the evidence currently of record.
Applicant also argues that none of the cited references offer any teaching on how many cells or how much rapamycin to include in a single spheroid, and in fact the concept of a spheroid with a defined cell count combined with a rapamycin drug payload is absent. Applicant asserts that Duan teaches the injection of mesenchymal stem cells and rapamycin separately, and Jhunjihunwala teaches rapamycin microparticle technology in isolation, and Kojima teaches how to form spheroids using microspheres but without disclosing the presence of rapamycin in the microspheres. Applicant therefore argues that the skilled artisan would not have immediately envisioned from the cited art dividing the recited number of cells into about 40 spheroids of 25,000 cell each and containing 0.1 micrograms of rapamycin. Applicant claims to have discovered that roughly 25,000 cells per spheroid is the optimal size yielding a potent immunosuppressive result, and that rapamycin at 100 ng per spheroid also renders the spheroid highly immunosuppressive while the use of e.g., 10 nm did not produce the same level of graft protection. Applicant points out that the rapamycin dosages recited by the cited art were for systemic administration while the claimed dosage per spheroid is a localized dose. Applicant concludes that arriving at the claimed amounts is not routine optimization because the cited art does not disclose any range for the number of cells or amount of rapamycin in a combined composition.
In response, while none of the cited references separately disclose the claimed combination of mesenchymal stem cells and rapamycin in a single spheroid, the references must be considered not individually but rather for what they suggest as a whole. Kojima’s disclosure that a spheroid composition comprising multicellular aggregates combined with microspheres has superior properties relative to unaggregated monolayer cells in terms of enhanced cell viability and function would have motivated the skilled artisan to combine the encapsulated rapamycin microparticles with the mesenchymal stem cells in a single spheroid instead of administering the cells and the rapamycin separately as taught by Duan. The skilled artisan further would have recognized that since the rapamycin is being administered along with the stem cells in individual spheroids instead of separately as in Duan would mean that the optimal amount of the rapamycin and amount of the cells per spheroid would have to be determined using an optimization process using the amounts taught by Duan as a starting point. While Applicant claims to have determined the optimal number of cells and drug per spheroid, such a determination does not by itself impart a patentable distinction to the claims, because there is no evidence of record that the amounts recited by the claims represent an unexpected criticality.
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 1-3 and 7-8 are provisionally rejected on the ground of nonstatutory double patenting as unpatentable over all claims of copending Application No. 19/056,005 in view of Duan et al. (Biochemical and Biophysical Research Communications 506 (2018) 619-625), Kojima et al. (Biomaterials 33 (2012) 4508-4514), and/or Jhunjhunwala et al. (J Control Release 2009 February 10; 133(3): 191-197) where indicated below.
This is a provisional nonstatutory double patenting rejection.
The teachings of the cited secondary references are relied upon as discussed above.
The reference claims recite a carrier comprising a mesenchymal stem cell conjugated with a drug carrier comprising rapamycin, wherein the carrier is prepared with PLGA, as well as a composition comprising the stem cell-drug carrier.
Although the reference claims do not recite that the carrier conjugate is in the form of spheroids comprising the stem cells and PLGA particles comprising the rapamycin, it would have been prima facie obvious to formulate the carrier in the form of such spheroids in light of Kojima’s disclosure that a cell composition comprising multicellular aggregate spheroids along with polymeric microspheres has superior properties relative to unaggregated monolayer cells, because aggregate formation enhances cell viability and function, such that the skilled artisan reasonably would have expected that forming hybrid spheroids comprising the mesenchymal stem cells and the rapamycin microparticles would improve the function of the mesenchymal stem cells upon transplant by promoting aggregation of the cells.
While the reference claims do not recite the amount of the rapamycin and polymer in the microparticles as recited by claim 2, it would have been prima facie obvious to select amounts of the rapamycin and polymer in the rapamycin particles to be within the claimed ranges, because Jhunijihunwala discloses that rapamycin particles having such proportions are suitable for use in delivering rapamycin to a subject.
The amounts of the mesenchymal stem cells and rapamycin recited by claim 1 is also prima facie obvious because Duan and Jhunjihunwala teach the use of amounts of mesenchymal stem cells and rapamycin and apportioning said stem cells and rapamycin to the spheroids in amounts within the ranges would have been within the purview of one of ordinary skill in the art. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
The resulting composition will suppress immune rejection of a transplant due to an increase in PD-L1 expression caused by the rapamycin microparticles as recited by claims 1 and 6 wherein the transplant is of any one or more of the cells recited by claim 7 such as stem cells based upon the evidence of record because it comprises the same ingredients in the same spheroid structure and a product cannot be separated from its properties. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01.
The claims are directed to an invention not patentably distinct from the claims of the copending application. Specifically, see above.
The USPTO may not institute a derivation proceeding in the absence of a timely filed petition. The U.S. Patent and Trademark Office normally will not institute a derivation proceeding between applications or a patent and an application of common ownership (see 37 CFR 42.411). The copending application, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case.
Response to Applicant’s Arguments
Applicant did not provide any substantive arguments against the rejection, which is therefore maintained.
Conclusion
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 GAREN GOTFREDSON whose telephone number is (571)270-3468. The examiner can normally be reached M-F 9AM-6PM.
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, David Blanchard can be reached on 5712720827. 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.
/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/ Primary Examiner, Art Unit 1600