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 .
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.
DETAILED ACTION
The amendments filed on 12/29/2025 which claims 1-2, 14-15, 19, 25, and 52-53 were amended is acknowledged. Claims 20, 33, and 36 were canceled.
Claims 1-5, 7-8, 12-15, 19, 24-25, and 51-53 are pending in the instant application.
Priority
This application is a 371 of PCT/US2020/049483, filed on 9/4/2020 which claims priority to the provisional applications 62935828 filed on 11/15/2019 and 62895787 filed on 9/4/2019.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-5, 7-8, 12-15, 19-20, 24-25, 33, 36, and 51) drawn to a method for increasing lymphocyte count in the reply filed on 6/30/2025 remains in effect. In their response applicant also elected the following species:
Length of A: 3 aa
IL-7 sequence: 70% SEQ ID NO: 1
Oligopeptide A sequence: Methionine-glycine-methionine (MGM)
Half-life extending domain: Fc region or fragment thereof
Patient status: has previously received 1+ cancer treatments
Il-7 conjugated dosage: about 1200 ug/kg
Dosing frequency: 1x per 6 weeks
Exclude residues 1-25 from SEQ ID NO: 1
After further consideration, there is no longer a search burden for the species described in part E and G; thus all species within E and G will be examined.
Claims 52-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/30/2025.
claims
Claims 1-5, 7-8, 12-15, 19, 24-25, and 51 are examined herein.
Withdrawn Objections
The objection to the claim 2 has been withdrawn; applicant added a semi-colon.
Withdrawn Rejections
The rejection of claim 14 under § 112(b) is withdrawn in light of the amendments; the claim no longer recites (cervix) in parentheses.
The rejection of claims 1-5, 7-8, 12-15, 19-20, 24-25, 33, 36 and 51 under § 112(b) is withdrawn in light of the arguments; applicant pointed to pg 13, para 0082 which states that the word “about” encompasses ranges ± 10% of the value. Claims 20, 33, and 36 were canceled.
The rejection of claim 19 under § 112(d) is withdrawn in light of the arguments; applicant argues that the dosages of claim 19 are suggested in the alternative. As a result certain dosages within the range of 600-1200 ug/kg described in claim 1 have been notched out in claim 19.
The rejection of claims 1-5, 7-8, 12-15, 19-20, 24, 33, and 51 under 102 has been withdrawn in light of the amendments; applicant incorporated the subject matter of claim 36 into the base claim which was rejected by a combination of references. Claims 20 and 33 were canceled.
Claim Rejections – 35 USC § 112(b)
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 1-5, 7-8, 12-15, 19-20, 24-25, 33, 36, and 51 are 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.
Claim 15
Claim 15 is drawn to the subject having previously received, currently receiving, or will receive a secondary treatment (i.e. surgery, radiation, chemotherapy). This claim is drawn to all possible states of receiving a secondary treatment, including not administering it, as the prognostic “will receive” could be applied to any subject. Because it is impossible to definitively predict future treatments the patient may receive, this claim is rendered indefinite. One of skill in the art would not be able to clearly predict the future of a patient’s treatment in order to determine if infringement upon the instantly claimed method occurred. Examiner recommends replacing “concurrently receives, or will receive one or more cancer treatments” with “or concurrently receives one or more cancer treatments”.
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.
Claims 1-5, 7-8, 12-15, 19, 24-25, and 51-53 are rejected under 35 U.S.C. 103 as being unpatentable over Yang (US20170158746) in view of Mgbemena (doi: 10.1016/j.celrep.2016.12.075) and Sheik (doi: 10.1182/blood-2015-05-645077).
*Claim 1, 19
Regarding claims 1 and 19, Yang teaches “IL-7 is a cytokine for promoting the survival and proliferation of T cells, B cells, and other immune cells, and it is an excellent candidate material for an immune therapeutic agent which is applicable in various diseases, such as viral infection, cancer, and immune system injury” (pg 1, para 0005). Yang teaches “the present invention provides an IL-7 fusion proteins, comprising a first domain comprising a polypeptide having the activity of IL-7 or a similar activity thereof; a second domain comprising an amino acid sequence having 1 to 10 amino acid residues consisting of methionine, glycine, or a combination thereof; and a third domain which prolongs the half-life of the interlenkin-7 fusion proteins” (pg 2, para 0018). Yang teaches “The modified IL-7 or an IL-7 fusion protein of the present invention may be administered for promoting the expansion or survival of naive or pre-existing T-cells or transplanted T-cells, or proliferating the in vitro isolated T-cell aggregates” (pg 6, para 0100). In sum, Yang teaches a method of administering a modified IL-7 complex of formula A-(IL-7)-X, wherein said modified IL-7 complex is administered for the purpose of expanding (a.k.a. increasing the count) of T-cells, which are a type of lymphocyte. Yang teaches the dosage is 0.01 mg/kg to 2 mg/kg (pg 7, para 0110), which corresponds to a range of 10 - 2000 ug/kg, absent evidence of criticality, this renders obvious the instantly claimed range of “about” 600-1200 ug/kg. See MPEP 2144.05(I) and MPEP § 2144.05(II)(A).
Yang is silent on the dosing frequency of the modified IL-7.
Sheikh teaches administering a recombinant human IL-7 (rhIL-7) to subjects with idiopathic lymphopenia via injection of once per week for three consecutive weeks (abstract; pg 978, col 1, para 2). Sheikh teaches the rhIL-7 is biologically active even at low doses and effective at stimulating T-cell proliferation and expansion (pg 986, col 1, para 3). Generally, differences in the dosage schedule will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such dosage schedule is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal dosage schedule of every 4 weeks instead of every 3 weeks as described by Sheikh is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A).
It would have been obvious to combine the teachings of Yang and Sheik because (1) Yang provides a modified IL-7 known to stimulate lymphocyte production; and (2) Sheik teaches a dosage regimen of rhIL-7 that is effective in stimulating lymphocyte production that is amenable to optimization or tailoring to the patient’s individual needs. One of skill in the art would have had a reasonable expectation of success because both the invention of Yang and Sheik are based on the biological activity of IL-7: the ability to increase lymphocyte count, and Sheik provides a working dosage regimen.
Claim 2
Regarding claim 2, Yang teaches the subject has cancer (pg 6, para 0101) and that the subject is optionally human (pg 6, para 0105).
Claim 3, 51
Regarding claims 3 and 51, Yang teaches the IL-7 shares 85% sequence identity to instant SEQ ID NO: 1 (SEQ ID NO: 24), shown below. Yang teaches the modified IL-7 is lacking residues 1-25 (underlined below) of instant SEQ ID NO: 1 (SEQ ID NO: 24).
instant_1 MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCL 60
Yang_24 ----------------------MGMDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCL 38
***********************************
instant_1 NNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQ 120
Yang_24 NNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQ 98
************************************************************
instant_1 VKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEH--- 177
Yang_24 VKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHRNT 158
*********************************************************
Claim 4-5
Regarding claims 4-5, Yang teaches the sequence MGM is linked to the N-terminus, as sequences are presented in N-to-C, shown above in bold (SEQ ID NO: 24).
Claim 7-8, 12
Regarding claims 7-8 and 12, Yang teaches the half-life extending domain of variable X is an Fc region comprising 100% sequence identity to instant SEQ ID NO: 9 (SEQ ID NO: 24; pg 4, para 0057), shown below.
instant_9 -----------------------------------RNTGRGGEEKKKEKEKEEQEERETK 25
Yang_24 SLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHRNTGRGGEEKKKEKEKEEQEERETK 180
*************************
instant_9 TPECPSHTQPLGVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA 85
Yang_24 TPECPSHTQPLGVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA 240
************************************************************
instant_9 KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ 145
Yang_24 KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ 300
************************************************************
instant_9 VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 205
Yang_24 VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 360
************************************************************
instant_9 SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 245
Yang_24 SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 400
****************************************
Claim 13-14
Regarding claims 13-14, Yang teaches the subject has cancer of the cervix, wherein “the cancer cells proliferated and exposed outside of the vaginal orifice” representing a type of solid tumor (pg 11, para 0169; pg 6, para 0101). Because claim 14 is rendered indefinite as discussed above, cancer of the cervix renders claim 14 obvious because the lining of the cervix contains neuroendocrine cells, thus satisfying the limitation of “neuroendocrine carcinoma (cervix)”.
Claim 15
Regarding claim 15, Yang teaches the modified IL-7 can be combined other drugs known to treat cancer (pg 1, para 0007; pg 7, para 0111-0112), thus meeting the limitation of the subject receiving concurrent chemotherapy.
Claim 24
Regarding claim 24, Yang teaches the modified IL-7 complex comprises instant SEQ ID NO: 24 (SEQ ID NO: 24, shown below).
instant_24 MGMDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLF 60
Yang_24 MGMDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLF 60
************************************************************
instant_24 RAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENK 120
Yang_24 RAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENK 120
************************************************************
instant_24 SLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHRNTGRGGEEKKKEKEKEEQEERETK 180
Yang_24 SLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHRNTGRGGEEKKKEKEKEEQEERETK 180
************************************************************
instant_24 TPECPSHTQPLGVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA 240
Yang_24 TPECPSHTQPLGVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA 240
************************************************************
instant_24 KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ 300
Yang_24 KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ 300
************************************************************
instant_24 VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 360
Yang_24 VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 360
************************************************************
instant_24 SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 400
Yang_24 SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 400
****************************************
*Claim 25
Regarding claim 25, Yang teaches that the subject is human (pg 6, para 0105).
Yang is silent on the total lymphocyte count of the patient before treatment.
Mgbemena teaches NCI’s CTCAE defines various grades of lymphopenia according to the total lymphocyte count (Table 2, reproduced below).
PNG
media_image1.png
224
1421
media_image1.png
Greyscale
In essence, the lowest grade of lymphopenia recognized is Grade I, denoted by a total lymphocyte count of LLN - 800 cells/mm3, which is equivalent to 999 - 800 cells/uL. This satisfies the limitation of “about 1000 lymphocyte cells or less/uL of blood” because the instant claim is drawn to the same NCI CTCAE grading system. As an evidentiary reference, Morales (doi: 10.1007/s00415-019-09557-w) teaches the LLN (Lower Limit of Normal) for lymphocytes is 1000 cells/uL, thus Grade I lymphopenia is defined as having 800-999 cells/uL of blood. See also CTCAE version 5.0 (dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-5x7.pdf), for supplemental definitions of grades of lymphopenia and other blood related abnormalities.
It would have been obvious to combine the teachings of Yang and Mgbemena because (1) Yang teaches the same modified IL-7 is effective at elevating lymphocyte counts; and (2) Mgbemena provides the diagnostic criteria of the CTCAE to identify what is considered a “low” lymphocyte count, thus identifying patients in need thereof of a lymphocyte-elevating treatment. One of skill in the art would have had a reasonable expectation of success because the NCI’s CTCAE standards establish a standard definition of the varying severities of lymphopenia, thus establishing a baseline for when medical intervention of administering a lymphocyte-elevating substance is necessary.
Double Patenting Rejections Not Made
U.S. Patent No. 10208099 and U.S. Patent No. 11041007 do not claim the half-life extending moiety of variable X.
Response to Arguments
Applicant’s arguments filed on 12/29/2025 have been fully considered but they are not persuasive.
112(b); pg 8, para 2
Applicant argues that the amendment adding “a surgery, radiation, chemotherapy, or combinations thereof” addresses the rejection of claim 15.
The issue at hand in the recitation of “will receive a chemotherapeutic” and not the material nature of the therapeutic. See the 112(b) rejection above.
103; pg 11, para 1
Applicant argues the references do not teach the newly added limitations regarding the dosing interval. Applicant argues that Yang teaches once every 3 weeks and Sheikh teaches once every week, both of which fail to teach once every 4-15 weeks as instantly claimed.
This has been addressed in the modified 103 rejection above. In essence, absent the evidence of criticality the instantly claimed dosages and dosage schedules could be arrived at via routine experimentation.
103; pg 6, para 1
Applicant argues that the reference of Sheik lacks both an oligopeptide and a half-life extending moiety. Therefore, the recombinant human IL-7 used in Sheikh is both structurally and functionally different from the modified IL-7 complex recited in claim 1 and could not be used to inform a dosage schedule. Applicant recognizes that Yang teaches the same modified interleukin-7 as claimed.
It is acknowledged that Shiekh does not provide the exact compound as instantly claimed, but is nonetheless considered relevant because it is drawn to teaching the administration hIL-7 to subjects with the same disease as instantly claimed. While Yang is silent on the particular dosage schedule, Yang teaches: “[the] dose may be determined depending on the types of diseases, health state of the patient, purpose of treatment or prevention, and other drug(s) or physiologically active material(s) to be administered in combination.” Thus Yang recognized at the time of filing that the dosage and dosage schedule is a result effective variable that is amenable to routine optimization. Absent evidence of criticality for the instantly claimed dosage schedules, one of skill in the art would have been able to arrive at an optimized dosage schedule given the disclosure of Yang and Sheik.
Conclusion
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 LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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