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
The preliminary amendment filed 12/06/2023 amended claims 1-7, and cancelled claims 8 and 10-11.
Claims 1-7, 9, and 12 are pending and examined on the merits herein.
Priority
This application claims the following priority:
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Claim Objections
Claim 3 is objected to because of the following informalities:
-In claim 3, Cay10598 and TCS2510 are synonyms. As such, either Cay10598 or TCS2510 should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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 1-7 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 colitis and a method of inducing revival stem cells by administering a composition comprising melatonin/melatonin receptor agonist and PGE2/PGE2 receptor agonist to a mammal or intestinal cells, does not reasonably provide enablement for a method of preventing or treating intestinal epithelial injury disease by administering a composition comprising melatonin/melatonin receptor agonist and PGE2/PGE2 receptor agonist. 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 criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claim encompass a method of preventing or treating any intestinal epithelial injury disease comprising administering a pharmaceutical composition comprising melatonin or any agonist of any melatonin receptor, and PGE2 or any agonist of PGE2 receptor.
Since the claim does not recite a population to which the composition is administered, the instant method encompasses any creature or cell that may develop any intestinal epithelial injury disease.
As such, the breadth of the claim is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with PhD.
State of the Prior Art
Nitta (Expression of the EP4 Prostaglandin E2 Receptor Subtype with Rat Dextran Sodium Sulphate Colitis: Colitis Suppression by a Selective Agonist, ONO-AE1-329, published 2002, PTO-892) teaches ONO-AE1-329, a PGE2 agonist, as an EP4 receptor agonist for the treatment of irritable bowel diseases and ulcerative colitis (title; abstract; pg. 70, Col. 1, Fig. 3; pg. 71, Fig. 4, Fig. 5; pgs. 72-73, Discussion).
Jiang (The prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration, The Jn of Pharma and Experimental Therapeutics, published 2007, PTO-892) teaches that melatonin reduces colitis (title). Jiang specifically teaches that administering melatonin to rat colitis models results in significant reduction of diarrhea and the loss of body weight (abstract).
Curtis (Ulcerative Colitis Prevention, PTO-892) teaches that there is no known way to prevent ulcerative colitis (pgs. 2, 5).
Thus, while the prior art teaches that it is known to treat colitis by administering prostaglandin EG2 agonists and melatonin, the art does not teach these compounds as treating any intestinal epithelial injury disease. Further, the art teaches that there is no known way to prevent ulcerative colitis.
Predictability in the Art
Ferretti (An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis, Jn of Clinical Medicine, published 2022, PTO-892) teaches that despite multiple medical therapies, surgery is the only curative treatment of ulcerative colitis (UC). However, Ferretti teaches that surgery is associated with a significant morbidity and mortality, as well as a risk of complication of an ileal pouch-anal anastomosis (pg. 1, paragraph).
Regarding therapeutic treatment, Ferretti teaches that a personalized approach with a careful assessment of negative prognostic factors and potential risk of under or over treatment is suggested in order to avoid negative outcomes and disease progression (pg. 3).
Regarding treatment with salicylates, Ferretti teaches that one of the major limitations is the degree of adherence to treatment, resulting in a worse long-term outcome (pg. 5). Regarding corticosteroids, Ferretti teaches that despite their role in the induction of UC remission and management of disease flares, corticosteroids are not indicated for maintaining remission due to their adverse events (pg. 6). Regarding calcineurin inhibitors, Ferretti teaches that due to the risk of adverse events, these compounds are limited to the induction of remission in acute severe-steroid-refractory UC or in thiopurine naïve patients with moderate to severe UC intolerance or refractory to corticosteroids (pg. 7). Regarding immunomodulators, Ferretti teaches that despite their effective role as steroid sparing agents and efficacy in maintaining remission, adverse events are a limiting factor, such as lymphoma (pg. 8). On pgs. 9-11, Ferretti continues to describe known UA treatments and their limitations and safety concerns.
In view of the teachings of Ferretti, it is not predictable to treat colitis with a pharmacological agent, let alone to prevent or treat any intestinal epithelial injury disease.
Working Examples
Example 1, beginning on pg. 13 of the specification. demonstrates confirmation of induction of revival stem cell population by treatment with melatonin and PGE2 in mouse intestinal epithelial organoids. Small-intestinal epithelial organoids from a mouse were treated with melatonin and PGE2 and microarray was performed to track gene expression changes, wherein PGE2 was shown to increase revival stem cell markers, especially in combination with melatonin.
Example 2, beginning on pg. 15 of the specification, demonstrates confirmation of induction of revival stem cell population by treatment with 8M-PDOT and Butaprost or Cay10598 in mouse intestinal epithelial organoids.
Example 3, beginning on pg. 16 of the specification, demonstrates confirmation of induction of revival stem cell population by treatment with melatonin or 8M-PDOT and Butaprost or Cay10598 in human intestinal epithelial organoids.
Direction and Guidance
In view of the working examples and the teachings of the specification, as a whole, the instant specification only provides direction and guidance in regard to a method of inducing revival stem cells in intestinal epithelial organoids by administering a combination of melatonin or 8M-PDOT and PGE2 or Butaprost or Cay10598.
Quantity of Experimentation
In view of the teachings of the prior art and the limited direction and guidance of the specification, the amount of experimentation required to determine which intestinal epithelial injury diseases are treated or prevented by which combination of melatonin or melatonin receptor agonists and PGE2 orPGE2 receptor agonist, would be astronomical, amounting to invention and not development; it is an undue amount of experimentation.
As such, while being enabling for a method of treating colitis and a method of inducing revival stem cells by administering a combination of melatonin or melatonin receptor agonist and PGE2 or PGE2 receptor agonist, the specification does not reasonably provide enablement for a method of preventing or treating intestinal epithelial injury disease by administering a composition comprising melatonin/melatonin receptor agonist and PGE2/PGE2 receptor agonist.
Claim Rejections - 35 USC § 103
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, 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, 3-7, 9, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over in Nitta (Expression of the EP4 Prostaglandin E2 Receptor Subtype with Rat Dextran Sodium Sulphate Colitis: Colitis Suppression by a Selective Agonist, ONO-AE1-329, published 2002, PTO-892) view of Jiang (The prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration, The Jn of Pharma and Experimental Therapeutics, published 2007, PTO-892).
Nitta teaches that prostaglandin E2, a prostaglandin E2 receptor, suppresses colitis and that administration of selective EP4 receptor agonists treats inflammatory bowel diseases such as colitis (abstract). Nitta specifically teaches ONO-AE1-329 as an EP4 receptor agonist for the treatment of irritable bowel diseases and ulcerative colitis (title; abstract; pg. 70, Col. 1, Fig. 3; pg. 71, Fig. 4, Fig. 5; pgs. 72-73, Discussion).
Regarding claims 1, 3, 7, 9, and 12, while Nitta teaches a method of treating colitis by administering ONO-AE1-329, it differs from that of instant claim 1 in that it does not teach a composition further comprising melatonin or an agonist of melatonin receptor.
Jiang teaches that melatonin reduces colitis (title). Jiang specifically teaches that administering melatonin in rat colitis models, results in significant reduction of diarrhea and the loss of body weight (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the methods of Nitta by adding the melatonin of Jiang, to arrive at a method of treating colitis by administering a composition comprising ONO-AE1-329 and melatonin. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-both Nitta and Jiang are directed toward methods of treating colitis, and
-"It 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). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such a modification to predictably arrive at a more potent and therapeutically effective method of treating colitis that reduces diarrhea and the loss of body weight.
Regarding claim 4, while the combination of Nitta and Jiang does not teach the µM amounts of melatonin or ONE-AEI-329, the optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
As such, an ordinary skilled artisan would have been motivated to make such µM selections to predictably arrive at the most therapeutically effective amounts of melatonin and ONE-AEI-329, to treat colitis.
Regarding claims 5 and 6, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04.
In the instant case, “wherein the pharmaceutical composition exhibits an effect of inducing revival stem cells,” in claim 5, and “wherein the pharmaceutical composition increases expression of one or more markers selected from the group consisting of clusterin, Ly6a and Claudin-4,” in claim 6, express the desired result of the positive step of administering the composition of claim 1. As such, these limitations are met by the combined method of Nitta and Jiang. See also MPEP 2112.02.
Further regarding claim 9, it is noted that the phrase “for inducing revival stem cells” is an intended use recitation. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. Since the combination of Nitta and Jiang teaches the instantly claimed composition, the composition of Nitta and Jiang is capable of performing the intended use, and therefore meets the intended use limitation of claim 9.
Further regarding claim 12, while the combination of Nitta and Jiang does not explicitly recite “inducing revival stem cells,” it recites the same method step of administering melatonin and ONE-AEI-329. As such, the combined method of Nitta and Jiang would necessarily induce revival stem cells following administration. It is further noted that this claim does not administer the active ingredients to any specific patient population, or population in general such as in vitro administration to cells.
Claim 2 are rejected under 35 U.S.C. 103 as being unpatentable over Nitta (Expression of the EP4 Prostaglandin E2 Receptor Subtype with Rat Dextran Sodium Sulphate Colitis: Colitis Suppression by a Selective Agonist, ONO-AE1-329, published 2002, PTO-892) and Jiang (The prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration, The Jn of Pharma and Experimental Therapeutics, published 2007, PTO-892). as applied to claims 1, 3-7, 9 and 12 above, and further in view of US 5,071,875 to Horn (published 1991, PTO-892).
Nitta and Jiang are applied as discussed above and incorporated herein.
While the combination of Nitta and Jiang teach a method of treating colitis by administering a composition comprising melatonin and ONE-AEI-329, it differs from that of instant claim 2 in that it does not teach 8MPDOT.
Horn teaches substituted 20amidotetralins as melatonin agonists and antagonists (title, abstract).
Horn teaches 8-methoxy-2-propionamidotetralin (8M-PDOT) as a preferred compound for use in a method for mimicking melatonin function (Col. 4, lines 50-58). Horn teaches that where it is desirable to mimic melatonin function, compounds such as 8M-PDOT, are administered (Col. 4, line 68-Col. 5, line3).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the melatonin in the combination of Nitta and Jiang with the 8-methoxy-2-propionamidotetralin (8M-PDOT) of Horn, to arrive at instant claim 2. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because Horn teaches 8M-PDOT as mimicking melatonin function and substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an ordinary skilled artisan would have reasonably expected 8M-PDOT to predictably treat colitis when combined with ONE-AEI-329.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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/LAUREN WELLS/Examiner, Art Unit 1622