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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114.
The Information Disclosure Statement (IDS) filed 30 October 2025 has been entered. Applicant’s amendments of the specification and claims filed 17 November 2025 have been entered. Applicant’s remarks filed 17 November 2025 are acknowledged.
Claims 2, 10 and 21 are cancelled. Claim 23 has been added. Claims 1, 3-9, 11-20 and 22-23 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 Claims 13-15 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.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, 3-9, 11-12, 16 and 22-23 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 Claims 1, 3-9, 11-12, 16 and 23 read on the elected species; and claim 22 is withdrawn as being drawn to non-elected species.
Specification
The objection to the specification for informalities in paragraph [0001] is withdrawn in response to Applicant’s amendment of the specification.
Claim Rejections Withdrawn
The rejection of claims 1-9, 11-12 and 16 under 35 U.S.C. 112(a), as failing to comply with the written description requirement, is withdrawn in response to Applicant’s amendment of independent claim 1 to recite “wherein the LIF is human LIF set forth in SEQ ID NO: 1 or a variant thereof which is at least 95% homologous thereto, or is an active fragment of LIF comprising SEQ ID NO: 2, or a variant thereof which is at least 95% homologous thereto”, and amendment of independent claim 16 to limit “administering a therapeutically effective amount of LIF”.
The rejection of claims 7-8 under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention, is withdrawn in response to Applicant’s amendment of the claims to delete the phrase “until symptoms of the disease are gone, the subject no longer responds to treatment or the symptoms of the disease have reached an acceptable level”.
The rejection of claims 1, 5-9, 11-12 and 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), in view of Basile et al. (US 2013/0243722 A1, Pub. Date: Sep. 19, 2013), is withdrawn in response to Applicant’s amendment of independent claim 1 to require “wherein the LIF is human LIF set forth in SEQ ID NO: 1 or a variant thereof which is at least 95% homologous thereto, or is an active fragment of LIF comprising SEQ ID NO: 2, or a variant thereof which is at least 95% homologous thereto”, and “wherein the LIF is administered as an enteric formulation or is formulated for topical administration to an area of the intestine”.
The rejection of claims 2-4 under 35 U.S.C. 103, as being unpatentable over Williams et al. (U.S. Patent No. 5,437,863), in view of Basile et al. (US 2013/0243722), and further in view of Durum et al. (US 20130164380 A1, Pub. Date: Jun. 27, 2013), is withdrawn in response to Applicant’s amendment of independent claim 1 to require “wherein the LIF is human LIF set forth in SEQ ID NO: 1 or a variant thereof which is at least 95% homologous thereto, or is an active fragment of LIF comprising SEQ ID NO: 2, or a variant thereof which is at least 95% homologous thereto”.
New Grounds of Objections/Rejections
Claim Objections
The following claims are objected to because of the informalities:
In claim 1, the phrase “the therapeutic amount LIF or variant thereof or a biologically active fragment of LIF or a variant thereof” should be “the therapeutically effective amount of the LIF”.
In claims 3-4 and 8, the term “LIF” should be “the LIF”.
In claims 6-7, 9 and 11-12, the phrase “the effective amount of LIF” and “the therapeutic amount LIF” should be “the therapeutically effective amount of the LIF”.
In claims 6 and 16, the word “about” should be deleted from the phrase “between about 1 mg/kg and 75 mg/kg”, and the word “between” should be added in the phrase “5 mg/kg and 50 mg/kg”.
In claim 7, it is suggested to express the unit as “mg/kg” such that it is consistent in the claims.
In claim 8, the word “or” should be added before “2 weeks to 4 weeks”.
In independent claim 16, it is suggested to include the full term of LIF, i.e., “leukemia inhibitory factor (LIF)”.
In claim 23, the phrase “wherein the LIF is human LIF set forth in SEQ ID NO: 1 or SEQ ID NO: 2” should be “wherein the LIF is human LIF set forth in SEQ ID NO: 1 or an active fragment thereof set forth in SEQ ID NO: 2”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected 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, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 recites administration routes which do not fall in the scope of claim 1, which recites “wherein the LIF is administered as an enteric formulation or is formulated for topical administration to an area of the intestine”. Therefore, the claim fails to further limit the subject matter of the claim upon which it depends
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Independent claim 16 is 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) (reference provided previously).
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, wherein the cytokine is administered simultaneously with, or subsequently to, the initiation of chemotherapy or radiation treatment; and wherein the treatment with the cytokine is continued until a healthy cell population is restored (col. 2, lines 8-45; also see claims). Williams teaches that the cytokine can be administered systemically, e.g., by subcutaneous, intraperitoneal, or intravenous 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).
While Williams does not specifically teach administering LIF daily at a dosage between 0.5-100 mg/kg, given that the level of skill in this art is very high, and that optimizing parameters, such as the dosage of a therapeutic agent and treatment frequency, is routine, modifying the dosage 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.
Amended claims 1, 3-9, 11-12 and 23 are 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 (Int’l. Pub. Date: 8 March 1990), and further in view of Durum et al. (US 20130164380 A1, Pub. Date: Jun. 27, 2013) (references provided previously).
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 wherein the LIF is human LIF set forth in SEQ ID NO: 1 or a variant thereof which is at least 95% homologous thereto (claim 1), wherein 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), wherein the LIF is administered as an enteric formulation for absorption by the small and large intestines (claims 1, 3-4), and wherein the effective amount of LIF administered per day is between 0.25-16 mg/kg or between 16-50 mg/kg (claims 7, 9).
WO 90/02183 teaches the amino acid sequence of human LIF, which is identical to SEQ ID NO: 1 of the instant application (see sequence alignment).
Durum further 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 polypeptides into the gastrointestinal tract of the subject, e.g., enteric-coated formulations and colonic formulations (ibid.). Durum also 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 modify the method of Williams by using human LIF having the amino acid of SEQ ID NO: 1 and administering 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 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., LIF, wherein the LIF is described in WO 90/02183 which has the amino acid sequence identical to SEQ ID NO: 1 of the instant application, 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.
Regarding administering the LIF 1 to 4 days, 7 days, 2 weeks, or up to 1 month before the subject receives radiation treatment, 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 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, 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 17 November 2025, Applicant argues that Williams particularly teaches using IL-11 as a treatment, however, IL-11 and IL-6 both promote inflammatory responses. Applicant argues that the Williams reference is outdated and largely incorrect, and a person of skill would have recognized this fact and not taken the reference at face value.
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). Thus, Williams’ teaching is not limited to IL-11 and IL-6, and Williams specifically teaches that LIF is useful as the treatment. Regarding Applicant’s arguments that Williams is outdated and largely incorrect, Williams teaches using the same therapeutic agent to treat the same patients as recited in the instant claims. Prior art does not lose its relevance simply because it is old, as long as it is within the field of invention.
Conclusion
NO CLAIM IS ALLOWED.
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