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
Response to Amendment
Applicant’s amendment of the claims filed 8 June 2026 has been entered. Applicant’s remarks filed 8 June 2026 are acknowledged.
Claims 2, 5, 10 and 21 are cancelled. Claim 24 has been added. Claims 1, 3-4, 6-9, 11-20 and 22-24 are pending. Claims 13-15 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1, 3-4, 6-9, 11-12, 16 and 22-24 are under examination to the extent they read on the elected species: A-a) wherein the subject is suffering from, or is at risk of developing, gastrointestinal radiation injury (GRI); and B-a) wherein the LIF or variant thereof, or a biologically active fragment of LIF or a variant thereof, is formulated for enteric absorption or as an enteric formulation. Claims 1, 3-4, 6-9, 11-12, 16 and 23-24 read on the elected species; and claim 22 is withdrawn as being drawn to non-elected species.
Claim Objections/Rejections Withdrawn
The objections to claims 1, 3-4, 8-9, 16 and 23 for various informalities are withdrawn in response to Applicant’s amendments of the claims.
The rejection of claim 5 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, is withdrawn in view that claim 5 is now cancelled.
The rejection of claim 16 under 35 U.S.C. 103, as being unpatentable over Williams et al. (U.S. Patent No. 5,437,863, Date of Patent: Aug. 1, 1995), is withdrawn in response to Applicant’s amendment of the claim to specify the amino acid sequence of the LIF.
Claim Objections/Rejections Maintained and New Grounds of Rejections
Claim Objections
The following claims remain objected for informalities that have not been corrected:
In claim 6, the word “between” should be added in the phrase “5 mg/kg and 50 mg/kg”.
In claims 7 and 11-12, the phrases “the therapeutically effective amount of LIF”, “the therapeutically effective amount of theLIF”, and “the therapeutic amount of LIF” should be “the therapeutically effective amount of the LIF”.
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.
Claims 3-4 are newly 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.
Claims 3-4 recite the limitation “wherein the enteric formulation of the LIF …”. There is insufficient antecedent basis for this limitation in the claims.
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.
Claims 1, 6-9, 11-12, 16 and 23 are newly rejected under 35 U.S.C. 103 as being unpatentable over Williams et al. (U.S. Patent No. 5,437,863, Date of Patent: Aug. 1, 1995), in view of WO 90/02183 (Int’l. Pub. Date: 8 March 1990) (both references provided previously).
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.
Williams teaches a method for treating a patient having damaged or depleted cell populations, e.g., small intestinal epithelial cells, epithelial cells lining the large intestine and stomach, or for treating a patient undergoing chemotherapy or radiation therapy, comprising administering to the patient an effective amount of a cytokine, wherein the cytokine is leukemia inhibitory factor (LIF), alone or in combination with additional cytokine(s) such as IL12 (col. 2, lines 8-45). Williams teaches that the LIF is described in WO 90/02183 (col. 3, lines 58-62). Williams teaches that the treatment begins concurrently with or shortly after the chemotherapy or radiation therapy and continues until a healthy cell population is restored; further, the cytokine or combination of cytokines may be administered for a suitable period of time prior to the beginning of chemotherapy or radiation therapy to improve the efficacy of stimulating the stem cell differentiation into the mature gut cell (col. 2, lines 17-26; col. 6, lines 28-37). Williams teaches that the cytokine can be administered by any suitable route, but is preferably administered systemically, e.g., by subcutaneous administration (bridging paragraph between col. 7-8). Williams teaches that a suitable treatment regimen for patients undergoing chemotherapy or radiation may be determined by the attending physician; generally, a suitable dose of the cytokine ranges between about 1 mg/kg body weight and about 1000 mg/kg body weight, and more preferably about 100 mg/kg; and these doses may be administered daily for between 1 day and 6 months, or for as long as is deemed necessary, depending on the nature of the cell damage or depletion (col. 8, lines 7-26).
Williams teaches as set forth above. Williams, however, does not teach the amino acid sequence of the LIF, which is as set forth in SEQ ID NO: 1 or a variant thereof which is at least 95% homologous thereto (claims 1, 16, 32), nor teaches that the LIF is administered 1 to 4 days, 7 days, 2 weeks, or up to 1 month before the subject receives radiation treatment (claim 1), and the amount of LIF administered per day is between 0.25-16 mg/kg or between 16-50 mg/kg (claims 7, 9).
Williams teaches that the LIF is described in WO 90/02183 (col. 3, lines 58-62). WO 90/02183 teaches the amino acid sequence of human LIF, which is identical to SEQ ID NO: 1 of the instant application (sequence alignment provided previously).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the LIF having the amino acid of SEQ ID NO: 1 in the method of Williams. One of ordinary skill in the art would have been motivated to do so, because Williams teaches a method for treating a patient undergoing chemotherapy or radiation and having damaged or depleted epithelial cells that line the small and large intestines, said method comprising administering to the patient an effective amount of a cytokine, e.g., the LIF described in WO 90/02183, and WO 90/02183 teaches the amino acid sequence of the LIF that is identical to SEQ ID NO: 1 of the instant application. Therefore, the combined teachings provide a reasonable expectation of success in treating the patient.
Regarding administering the LIF 1 to 4 days, 7 days, 2 weeks, or up to 1 month before the subject receives radiation treatment as recited in claim 1, Williams teaches administering the cytokine (e.g., LIF) for a suitable period of time prior to the beginning of chemotherapy or radiation therapy to improve the efficacy. Given that the level of skill in this art is very high, and that optimizing parameters, such as administration schedule of a therapeutic agent, is routine, modifying the method of Williams to administer the LIF 1 to 4 days, 7 days, 2 weeks, or up to 1 month prior to the beginning of chemotherapy or radiation therapy to thereby improve the efficacy would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, with a reasonable expectation of success, absent evidence of unexpected results. As was found in In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), where the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding administering the LIF daily in an amount between 0.25-16 mg/kg or between 16-50 mg/kg as recited in claims 7 and 9, Williams teaches that a suitable dose of the cytokine, e.g., LIF, ranges between about 1 mg/kg body weight and about 1000 mg/kg body weight, and more preferably about 100 mg/kg, and these doses may be administered daily for between 1 day and 6 months, or for as long as is deemed necessary, depending on the nature of the cell damage or depletion. Given that the level of skill in this art is very high, and that optimizing parameters, such as the dose(s) of a therapeutic agent, is routine, modifying the dose(s) of LIF used in the method of Williams to arrive at the presently claimed ranges would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, with a reasonable expectation of success, absent evidence of unexpected results. As was found in In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), where the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Response to Applicant’s Arguments
In the response received on 8 June 2026, Applicant argues that Williams teaches the use of cytokines, particularly, IL-11, for administration to subjects undergoing radiation therapy; while LIF is described only as a cytokine that shares IL-11 signal transduction pathway as described in WO 90/02183, no examples are provided showing any activity of LIF or that it was useful in the methods described. Applicant further argues that WO 90/02183 teaches the protein as having differentiation inhibitory activity useful in culturing stem cells in vitro, but does not include any concrete suggestion of potential use as a treatment as claimed in the present invention. Applicant argues that neither Williams nor WO 90/02183, alone or in combination, suggested to the person of skill that this protein could be effective in the method claimed with a reasonable expectation of success.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
Williams teaches a method for treating a patient having damaged or depleted cell populations, e.g., small intestinal epithelial cells, epithelial cells lining the large intestine and stomach, or for treating a patient undergoing chemotherapy or radiation therapy, comprising administering to the patient an effective amount of a cytokine, and Williams specifies that the cytokine is selected from the group consisting of interleukin-11, interleukin-6, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor (see claims). Williams teaches that the LIF is described in WO 90/02183 (col. 3, lines 58-62), and WO 90/02183 teaches the amino acid sequence of the LIF which is identical to SEQ ID NO: 1 of the instant application. Thus, Williams’ teachings are not limited to IL-11, and Williams specifically teaches and suggests that the LIF of SEQ ID NO: 1 is also useful as the treatment. With respect to Applicant’s argument that Williams does not provide examples showing any activity of LIF or that it was useful in the methods described, Williams expressly teaches that the LIF as described in WO 90/02183 is useful as the treatment in the method, thus, Williams, in combination with WO 90/02183, make obvious of the claimed invention. Further, Applicant acknowledges that the prior art describes the LIF as a cytokine that shares IL-11 signal transduction pathway, given the examples that showed IL-11 to be useful in the treatment method, the person of skill would recognize that the LIF protein would also be effective in the claimed method with a reasonable expectation of success.
Claims 3-4 remain rejected under 35 U.S.C. 103 as being unpatentable over Williams et al. (U.S. Patent No. 5,437,863), in view of WO 90/02183, and further in view of Durum et al. (US 20130164380 A1, Pub. Date: Jun. 27, 2013).
Applicant argues that Durum does not make up for the failure of the previously discussed references to teach or suggest all claim elements, and does not add to the fair suggestions to the person of skill that would be required to achieve the present claims.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
Applicant’s arguments with regard to the Williams and WO 90/02183 references have been addressed above. Durum is cited to remedy the deficiencies in Williams and WO 90/02183 to provide teachings that the LIF is formulated for absorption by the small or large intestine (claims 3-4).
Durum teaches methods suitable for delivering polypeptide agents (e.g., IL-27) into the gastrointestinal tract of a subject, e.g., for treating a person having inflammatory bowel disease [0140]. Durum teaches using microparticles having a coating that provides localized release of the polypeptide agent into the gastrointestinal tract of the subject, e.g., enteric-coated formulations and colonic formulations (ibid.). Durum teaches that the formulations can be administered orally [0182].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Durum to administer the LIF to the gastrointestinal tract of the subject in need of the treatment. One of ordinary skill in the art would have been motivated to do so, because Williams in combination with WO 90/02183 teach and suggest a method for treating a patient undergoing chemotherapy or radiation and having damaged or depleted epithelial cells that line the small and/or large intestines, said method comprising administering to the patient an effective amount of a cytokine, e.g., LIF of SEQ ID NO: 1, and Durum further teaches methods suitable for delivery of polypeptide agents into the gastrointestinal tract of a subject by using enteric-coated formulations or colonic formulations. Therefore, the combined teachings provide a reasonable expectation of success in treating the patient.
Allowable Subject Matter
Claim 24 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
NO CLAIM IS ALLOWED.
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 Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. 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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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674
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