DETAILED OFFICE ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The request filed on 18 June 2025 for a Continued Examination (RCE) under 37 CFR 1.114 based on parent Application No. 17/667,885 is acceptable, and an RCE has been established. An action on the RCE follows.
Applicant’s amendment filed on 23 September 2025 is acknowledged and entered. Following the amendment, claim 1 is amended.
Currently, claim 1 is pending and under examination.
Formal Matters:
Information Disclosure Statement
Applicant's IDS submitted on 6/18/2025 is acknowledged and has been considered. A signed copy is attached hereto.
Rejections under 35 U.S.C. §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.
Written Description/New Matter
Claim 1 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The amended claim 1 recites “at least 1 ug/mL” (infliximab) in lines 4-5. However, while applicant pointed out the support in the specification ([0039]), the examiner is not able to locate the support for the limitation. According to the specification (where the concentration of infliximab is mentioned in paragraph [0039]), “[E]xisting studies recommend 3 to 10 μg/mL as the therapeutic blood concentration of infliximab. In the present invention, the concentration of infliximab in medium was set to a low concentration (1 μg/mL) and a high concentration (10 μg/mL), and it was confirmed that the cellular response of intestinal epithelial organoids by TNFα was inhibited and the epithelial regenerative ability was restored. Infliximab at a low concentration (1 μg/mL) in Crohn's disease patient-derived intestinal organoids did not completely restore the TNFα-induced organoid reconstitution rate. In the case of treatment with a high concentration (10 μg/mL) of infliximab, the organoid reconstitution rate, cell proliferation ability and wound healing ability could be restored to normal levels.” The blood concentration or medium concentration of infliximab is a different concept as to the infliximab concentration in a pharmaceutical composition. Therefore, clearly, said support as pointed out by applicant cannot be used to support the limitation of “at least 1 ug/mL” (infliximab) in the claimed pharmaceutical composition; and the limitation of “at least 1 ug/mL” constitutes new matter.
In addition, with respect to the lack of written description rejection set forth in the previous Office Action, applicants argument filed on 23 September 2025 has been fully considered, but is not deemed persuasive for the reasons below.
At pages 5-6 of the response, the applicant argues that to address the point regarding organoid models, Sugimoto et al. discuss the advantages of organoid culture systems, patient-derived organoid experiments often represent the closest option to in vivo experimentation available, for human patient-targeted therapies in particular; that claim 1 as presented herein is drawn to the particular TNFa inhibitor infliximab, and to a dose range commensurate with the exemplified data of the application as filed; that to address the point regarding a perceived lack of supporting experimental evidence, the specification shows experimental results (organoid reconstitution and cell survival) for the combination of 1 ug/mL infliximab and 5 nM PGE2 compared with those for 10 ug/mL infliximab or 10 nM PGE2 ([0046], Fig. 17 - 19), wherein the combination provides meaningful and statistically supported improvement in organoid reconstitution rate and cell proliferation ability; that the present inventors proposed the combination of PGE2 with TNFa inhibitors for inflammatory bowel disease to enhance damaged intestinal mucosal reconstitution and improve mucosal healing ability; and this invention is therefore the first to disclose and support the specific combination of low-dose infliximab with PGE2 for this purpose.
This argument is not persuasive for the reasons of record, and the following: first, Sugimoto also teaches that “[A]lthough intestinal organoids derived from adult human tissues emulate the diversity of in vivo intestinal epithelial cell types, it is true that they lack vascularization, neural innervation, fluid flow, interactions with other cells, and intestinal luminal contents. To understand these complicated interactions between epithelium and nonepithelial cells, mouse models are currently the best experimental platform. …, it remains undetermined to what extent these coculture systems recapitulate the heterocellular interactions in vivo, and further optimization is required to tackle this challenge through the development of advanced culture platforms” (page 2021, 1st column, 2nd paragraph). Clearly, the organoid model cannot replace the in vivo animal model for the real world use yet (clinical pathology and drug efficacy, for example). Further, more importantly, the issue here is not lack of enablement, rather, the issue is that the specification does not provide adequate written description for the claimed genus of the pharmaceutical composition of infliximab and PGE2 at the ratio as claimed. Even if the organoid model were considered a viable model for IBD, the specification merely discloses one single species for the claimed genus. Therefore, once again, the specification does not provide a representative number of species falling within the scope of the genus; and one of skill in the art would not conclude that the applicant was in possession of the claimed genus of the pharmaceutical composition for treating IBD based on the disclosure of the present application. The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. Furthermore, with respect to the argument that the present inventors proposed the combination of PGE2 with TNFa inhibitors for IBD; and this invention is therefore the first to disclose and support the specific combination of low-dose infliximab with PGE2 for this purpose, such is less relevant here because, once again, the issue is that the specification does not provide adequate written description for the genus as claimed; and the limitations of “at least 1 ug/mL” and “at a weight ratio of 1:100” are not exactly low-dose infliximab if “571” in “1: 571” represents 1 ug/ml infliximab in blood (see specification, page 16, [0046], for example) (though the claim is indefinite and confusing, and such is not the same as a treatment dose).
Rejections under 35 U.S.C. §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.
Claim 1 is 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 pre-AIA the applicant regards as the invention.
Claim 1 is indefinite for the recitation “infliximab in an amount of at least 1 ug/mL” because it is unclear what “an amount of at least 1 ug/mL” is meant, as “ug/mL” represents a concentration, not “an amount”. The claim is further indefinite because there is no upper
limit for the concentration (open-ended range), and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The metes and bounds of the claim, therefore, cannot be determined.
Prior Art Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 of this title, 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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Centocor Ortho Biotech Inc. (REMICADE (infliximab), HIGHLIGHTS OF PRESCRIBING INFORMATION, 2011), and Peng et al. (Sci Rep. 2017 Apr 21;7(1):1055),
The teachings of Centocor Ortho Biotech Inc., and Peng were reviewed in the previous Office Action, and are paraphrased herein:
Centocor Ortho Biotech Inc. discloses highlights of prescribing information for REMICADE (infliximab), wherein REMICADE (infliximab) is indicated for the use of treating diseases including Crohn’s Disease and Ulcerative Colitis (page 1, 1st column, under “INDICATIONS AND USAGE”), both of which are inflammatory bowel disease.
Peng teaches that COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC); and the experimental results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis, thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC (abstract, for example); and that the study revealed that PGE2 treatment helps to maintain colonic epithelial barrier integrity, and recovers normal expression and distribution of proteins by COX-1/PGE2/EP4 up-regulation of β-arr1/p-Akt signaling, suggesting that PGE2 has a favorable therapeutic effect on DSS-induced ulcerative colitis, supporting its future development and clinical application in inflammatory bowel disease (page 9, 2nd paragraph, for example).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to make a pharmaceutical composition comprising a tumor necrosis factor alpha inhibitor such as infliximab and PGE2 for treating inflammatory bowel disease following the teachings of Centocor Ortho Biotech Inc. and Peng. The person of ordinary skill in the art would have been motivated to make such a pharmaceutical composition for disease treatment such as IBD, and reasonably would have expected success because both infliximab and PGE2 can be used for treating IBD; and Peng has demonstrated that PGE2 has a favorable therapeutic effect on DSS-induced ulcerative colitis.
With respect to the limitation of the PGE2 and infliximab weight ratio of 1:100 to 1:571, as the prior art references teach that both PGE2 and infliximab could be used for the same purpose (treating IBD), "[I]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See also, MPEP 2144.06 I. As such, it would be obvious to combine PGE2 and infliximab at various ratios, unless unexpected result (synergy, for example) is demonstrated for a particular ratio, which does not seem to be the case here.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion:
No claim is allowed.
Advisory Information:
Any inquiry concerning this communication should be directed to Examiner DONG JIANG whose telephone number is 571-272-0872. The examiner can normally be reached on Monday - Friday from 9:30 AM to 7:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DONG JIANG/
Primary Examiner, Art Unit 1674
9/26/25