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 .
Claims 1,3-5,7-10 are under examination.
Response to Applicants’ Arguments/Amendments
Applicants have amended the claims to better clarify the relationship of the therapeutic cells to the actual patient. As a result of the amendments, the 112(b) rejection is withdrawn. The other rejections are maintained and arguments against the remaining rejections are addressed below the rejections.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1,3-5,7-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating diabetes caused by an immune checkpoint inhibitor comprising administering an effective amount of mesenchymal stem cells intraperitoneally/systemically to a patient in need, does not reasonably provide enablement for a method for preventing and/or treating diabetes caused by an immune checkpoint inhibitor, comprising administering an effective amount of mesenchymal stem cells to a patient in need. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988).
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experiment to make and use the invention based on the content of the disclosure is undue.
Nature of the Invention:
The method involves treating and/or preventing diabetes caused by an immune checkpoint inhibitor by administering an effective amount of mesenchymal stem cells to a patient in need.
Breadth of the Claims:
The claims recite both methods of treating and preventing diabetes caused by a checkpoint inhibitor. A treatment can cause any type of benefit/positive result. The term prevention recited in the claims means that diabetes caused by an immune checkpoint inhibitor is always prevented from occurring by administering an effective amount of mesenchymal stem cells. The claims also encompass any method of administration.
Teachings from the Art:
Kawada-Horitani et al. “Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade” Diabetologia (2022) 65: 1185-1197 teaches mesenchymal stem cells can be successfully used as a treatment for diabetes caused by checkpoint blockade (Page 1189). However, Kawada-Horitani et al. teaches that when mesenchymal stem cells are administered, the mesenchymal stem cells do not always prevent diabetes. In the results section on page 1189, Kawada-Horitani teaches that “hMSC administration decreased the incidence of overt diabetes to four of 21 (test subjects).” Diabetes still occurred in 4 animals; diabetes was not completely prevented.
Kawada-Horitani et al. teaches that mesenchymal stem cells are injected using a 27G needle through the tail vein of mice (intraperitoneal method). Kawada-Horitani does not support other methods of administration.
Applicants Specification/Guidance/Working Examples
The specification does not show that diabetes is completed prevented. Figure 2 of the specification shows that the incidence of diabetes even with mesenchymal stem cell administration is still around 20% (Figure 2).
Furthermore, Example 1 of the specification teaches that the mesenchymal stem cells are administered in the tail vein (intraperitoneal administration). Other methods such as topical administration of mesenchymal stem cells to feet are not disclosed.
Conclusion
Both the specification and art only teach treatment of diabetes and not prevention because the specification and art do not teach absolute prevention. Even with administration of mesenchymal stem cells, the incidence of diabetes is still about 20% (not complete prevention). Furthermore, the specification and art only teach intraperitoneal administration not other methods of administration such as topical administration to feet. It is not clear how topical administration or other forms of administration of mesenchymal stem cells besides intraperitoneal administration would treat diabetes. Furthermore, non-routine and undue experimentation would be needed to make all conceivable methods of administration useful to treat diabetes caused by checkpoint inhibitors.
Response to Applicants’ Arguments
The examiner has considered applicants arguments. The clam term “prevention” means that the diabetes would never occur. The specification does not show that administration of the mesenchymal stem cells always prevents the occurrence of diabetes. Figure 1 does not show that diabetes is always prevented. What Figure 1 is showing is a reduction in the occurrence of diabetes. Reduction is the more appropriate term to use instead of prevention.
The claims are so broad that they encompass any method of administration. The method of administration includes putting the mesenchymal cells in a foot cream and applying the cream to feet to treat diabetes. This method isn’t going to be effective. Applicants need to amendment the claims to state that the composition is administered systemically.
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 1,3-5,7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Yoneda et al. “T-Lymphocyte Infiltration to Islets in the Pancreas of a Patient Who Developed Type 1 Diabetes After Administration of Immune Checkpoint Inhibitors” Diabetes Care, Volume 42, July 2019 in view Shaked (WO 2020049552)
Yoneda acknowledges that anti-PD-1 antibody (an anti-cancer agent) administration without mesenchymal stem cells is associated with the development of diabetes (introduction, 2nd paragraph and Conclusion (e118). Yoneda does not offer any teaching and/or insight for ameliorating the negative side effects such as diabetes associated with anti-PD-1 antibody treatment. However, Shaked teaches a method for ameliorating such negative side effects. Shaked teaches that mesenchymal stem cells activated with an anti-cancer agent can be used to treat diseases/conditions such as diabetes(Abstract, Paragraphs 6, 36,43-44,80) as in instant Claims 1,3.
Dependent Claims taught by Shaked
Shaked teaches that the mesenchymal stem cells are allogenic to a subject (Paragraph 34) as in instant Claims 4 and 7. Shaked teaches wherein the mesenchymal stem cells are derived from bone marrow (Paragraph 93) as in instant Claims 5 and 8-10.
Yoneda teaches that a problem with anti-PD-1 antibody (an anti-cancer agent/immune checkpoint inhibitor) treatment is that patients are prone to developing diabetes (1st page of Yoneda). Yoneda fails to disclose a method of decreasing the occurrence of diabetes. However, Shaked teaches that activated mesenchymal stem cells can treat conditions such as diabetes. An artisan would have been motivated to have treated diabetes caused by immune checkpoint inhibitors with activated mesenchymal stem cells since they are known to be able to treat and reduce the occurrence of unwanted conditions/disease such as diabetes. Given the teachings of the cited references and the level of skill of an artisan at the time of applicants’ invention, it must be considered absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All of the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSA International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007)). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.'s and Ph.D.'s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, oncology treatments, and immunotherapy.
Response to Arguments
Applicants argue the following in italics, “Yoneda et al. does not disclose administering MSCs to treat diabetes as a side effect caused by ICI administration. Shaked et al. describes activation of cells by anticancer agents. In contrast the present invention does not use MSCs that have been activated by anticancer agents; therefore, the two focus on entirely different aspects. Furthermore, Shaked does not teach or suggest that administration of MSCs is effective in treating diabetes as a side effect following immune checkpoint inhibitor therapy.”
In the rejection, the Yoneda reference is part of the rejection because it teaches that anti-PD-1 antibody (an anti-cancer agent) can cause the development of diabetes. When diabetes occur, the diabetes needs to be treated which is why Shaked is cited. Shaked teaches that mesenchymal stem cells can be used to treat diabetes (Paragraphs 43-44). There has been no evidence cited by applicant that the diabetes caused by an anti-PD-1 antibody is significantly different than the diabetes cited in the Shaked reference. The specification and the prior art do not teach a specific type of diabetes that results from treatment with immune checkpoint inhibitors. Therefore, it would have been obvious to have treated the diabetes caused by an anti-PD-1 antibody with the mesenchymal stem cell composition taught by Shaked since the composition can treat diabetes. The transition term of the claims is “comprising” which means that other agents can be included.
Applicants argue that “diabetes induced by immune checkpoint inhibitors is a disease distinct from conventional diabetes.” However, applicants have not actually presented evidence that shows how diabetes induced by immune checkpoint inhibitors differ from conventional diabetes. In the remarks section applicants mention Reference A (provided by applicants) Kyriacou et al. “Is immune checkpoint inhibitor-associated diabetes the same as fulminate type 1 diabetes melitus?” (Clinical Medicine 2020, Vol 20, No. 4, 417-23). Applicants discuss evidence in Kyriacou that the diabetes caused by the immune checkpoint inhibitors may or may not be fulminant type 1 diabetes or a type of diabetes related to fulminant type 1 diabetes (Table 1); however, applicants do not identify a specific distinct type of fulminant type 1 diabetes that is caused by immune checkpoint inhibitors. Applicants further argue, “Our review shows that ICI-induced diabetes is a different entity to FTIDM, at least for the majority of patients with this condition.” The reference shows that immune checkpoint inhibitors are not necessarily FTIDM; however, reference A and reference B (both provided by applicants) failed to identify a specific type of diabetes that the immune checkpoint inhibitors cause which would be distinct from conventional diabetes.
Applicants further argue that both references C and D (both provided by applicants) dissuade an applicant from using mesenchymal stem cells to treat diabetes resulting from immune checkpoint inhibitors. Applicants further argue that, “while immune checkpoint inhibitors act to enhance T cell immunity, MSCs act in the opposite direction by suppressing T cell immunity and inducing or activating T regs.” Applicants are arguing that immune checkpoint inhibitors and MSC have counter effects in the body and thus, an artisan would not have been motivated to have used mesenchymal stem cells to treat diabetes resulting from use of immune checkpoint inhibitors.
This argument is not commensurate with the scope of the instant claims. The claim is not requiring that the immune checkpoint inhibitor and the mesenchymal stem cells are administered at the same time. The immune checkpoint inhibitors can be administered before administration of the mesenchymal stem cells so the therapies do not conflict with one another. The mesenchymal stem cells can be administered weeks after diabetes has occurred from the previous administration of immune checkpoint inhibitors. Therefore, the administration of the immune checkpoint inhibitors and the mesenchymal stem cells does not necessarily cause a conflict.
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 1,3,5, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,179,420 in view of Yoneda et al. “T-Lymphocyte Infiltration to Islets in the Pancreas of a Patient Who Developed Type 1 Diabetes After Administration of Immune Checkpoint Inhibitors” Diabetes Care, Volume 42, July 2019 and Shaked (WO 2020049552)
Claim 1 of 11,179,420 is so broad that it encompasses using mesenchymal stem cells to treat any disease or medical condition using any method of administration. Instant claim 1 is a species of claim 1 of 11,179,420 because the instant claim recites treating diabetes which is a specific type of disease/medical condition that is treated by administering mesenchymal stem cells.
Furthermore, Yoneda teaches that an immune checkpoint inhibitor such as an anti-PD-1 antibody (mentioned in instant claim 3) is associated with causing diabetes when administered (Page e116). Shaked teaches a method for ameliorating such a negative side effect. Shaked teaches that mesenchymal stem cells from bone marrow (mentioned in instant claim 5) can be used to treat diseases/conditions such as diabetes(Abstract, Paragraphs 6, 36,44,80). These references teach using mesenchymal stem cells to treat diabetes which is a specific disease/medical condition.
Instant claim 1 recites a method for treating diabetes caused by an immune checkpoint inhibitor. Instant claim 1 is a species of claim 1 of Patent 11,179,420 because claim 1 of Patent 11,179,420 is so broad that it encompasses the treatment of any disease or medical condition, including diabetes, using mesenchymal stem cells. Many prior art references exist which teach administering mesenchymal stem cells to treat diseases/medical conditions. Shaked teaches that diabetes can be treated by administering mesenchymal stem cells. Because claim 1 of Patent 11,179,420 also encompasses administering mesenchymal stem cells to treat diabetes, a terminal disclaimer for Patent 11,179,420 is needed.
Response to Applicants Arguments
Applicants argue that the diabetes treatment recited in the instant claims is directed to specific type of diabetes that is caused by immune checkpoint inhibitors. Applicants further argue that the obviousness type double patenting rejection was not appropriate because the conditions/diseases recited in the claims of Patent 11,179,420 is broadly claimed without specifically mentioning any particular type of diabetes by name. Skaked, part of the rejection, teaches that mesenchymal stem cells can treat diabetes. As discussed above, applicant has not identified a distinct type of diabetes that results from the use of immune checkpoint inhibitors.
Conclusion
All claims stand rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638