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
Claims 1-33, 35-39, and 41-46 are pending in the instant application.
Priority
This application claims priority to the provisional applications 63502746 filed on 5/17/2023, 63481630 filed on 1/26/2023, and 63352842 filed on 6/16/2022.
Election/Restriction
After further consideration, there is no longer a search burden for the species of antibodies and hIL-2 variants described in 1-33, 35-39, and 41-46; thus these species will be examined.
Applicant’s election without traverse of Group III (claims 23-33, 35-39, and 41) in the reply filed on 2/17/2026 is acknowledged.
Claims 1, 8, 17, and 24 were found allowable. Claims 1-22, and 42-46, previously withdrawn from consideration as a result of a restriction requirement, requires all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between inventions (I)-(V), as set forth in the Office action mailed on 12/19/2025, is hereby withdrawn and claims 1-22, and 42-46 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 1-33, 35-39, and 41-46 are examined herein.
Information Disclosure Statement
The information disclosure statements (IDS) dated 8/23/2024, 9/10/2024, 9/26/2024, and 11/7/2024 comply with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Claim Rejections – 35 USC § 112(d)
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.
Claims 4-5, 12-15, 31-33, 41, and 45-46 are 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 4-5
Claims 4 and 5 are drawn to the sequence, SEQ ID NO: 345, further comprising a deletion or substitution at position 3 and/or position 125. This expands the scope over parent claim 1, which does not include such a mutation. Examiner recommends amending parent claim 1 to include the language of “optionally comprising a substitution or deletion at position 3 and/or position 125”.
Claim 12-15
Claims 12-15 are drawn to the sequence, SEQ ID NO: 345, further comprising a deletion or substitution at position 3 and/or position 125. This expands the scope over parent claim 8, which does not include such a mutation.
Claim 31-32
Claims 31-32 are drawn to the sequence, SEQ ID NO: 345, further comprising a deletion or substitution at position 3 and/or position 125. This expands the scope over parent claim 24, which does not include such a mutation. The mutated residues of SEQ ID NO: 217 are underlined in gray below (SEQ ID NOs: 215-216 and 218-219 are shown in the 112(d) rejection of claim 33).
>instant_217
10 20 30 40 50 60
APASSSTKKT QLQLEHLLLA LQMILNGINN YKNPKLTEML TFKFYMPKKA TELKHLQCLE
70 80 90 100 110 120
EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR
130
WITFAQSIIS TLT
Claim 33
Claim 33 is drawn to (i) SEQ ID NOs: 215-216 which include mutations outside of residues 20 and 38; and (ii) SEQ ID NOs: 218-219 are lacking the first three residues of the sequence when aligned according to SEQ ID NO: 345. The missing residues have been denoted with letter X. These sequences represent an expansion of scope as they include substitutions and deletions not claimed within parent claim 24. The mutated residues are underlined in gray below.
>instant_215
10 20 30 40 50 60
APTSSSTKKT QLQLEHLLLA LQMILNGINN YKNPKLTEML TFKFYMPKKA TELKHLQCLE
70 80 90 100 110 120
EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR
130
WITFAQSIIS TLT
>instant_216
10 20 30 40 50 60
APASSSTKKT QLQLEHLLLA LQMILNGINN YKNPKLTEML TFKFYMPKKA TELKHLQCLE
70 80 90 100 110 120
EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR
130
WITFCQSIIS TLT
>instant_218
10 20 30 40 50 60
XXXSSSTKKT QLQLEHLLLA LQMILNGINN YKNPKLTEML TFKFYMPKKA TELKHLQCLE
70 80 90 100 110 120
EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR
130
WITFCQSIIS TLT
>instant_219
10 20 30 40 50 60 XXXSSSTKKT QLQLEHLLLA LQMILNGINN YKNPKLTEML TFKFYMPKKA TELKHLQCLE 70 80 90 100 110 120 EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR 130 WITFAQSIIS TLT
Claim 41
Claim 41 is drawn to a composition comprising no other components other than the immunoconjugate described in parent claim 24. Thus claim 41 fails to further limit parent claim 24. Examiner recommends including “and a pharmaceutically acceptable carrier” to the claim. Dependent claims 45-46 fail to cure these deficiencies, thus are also rendered indefinite.
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 § 112(a)
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.
Claim 45 is 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 treating cancer, does not reasonably provide enablement for treating any and all diseases. 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.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Claim 45
Nature of the invention/Breadth of claims:
Claim 45 is drawn to treating any disorder or disease using a fusion protein combining (i) an anti-PD1 antibody and (ii) a modified human IL-2.
State of the prior art/Predictability or unpredictability of the art:
Jiang (doi: 10.1080/2162402X.2016.1163462) teaches IL-2 is one of the key cytokines with pleiotropic effects on the immune system that is effective in treating metastatic cancers such as melanoma (abstract). Jiang teaches IL-2 can be combined with anti-PD1 antibodies to produce synergistic anti-cancer effects (pg 4, col 2, para 3). Absent the evidence that either of these compounds are effective for treating any and all disease when combined, one of skill in the art would have no reasonable expectation that the instantly claimed fusion proteins would be effective for treating non-cancer diseases such as post-traumatic stress disorder, diabetes, muscular dystrophy, or chronic traumatic encephalopathy.
Amount of guidance/Existence of working examples:
The instant specification describes administering the fusion protein to a colorectal cancer model (Example 23). Applicant does not describe administering the fusion protein to any non-cancer disease types.
Quantity of experimentation:
Given (i) the variety in diseases and their underlying etiologies; and (ii) the absence of evidence of the fusion protein or either of its components being effective for treating non-cancer diseases, a person of skill in the art, in undertaking the experimentation necessary to determine which diseases could be treated by the fusion protein, would have no reasonable expectation that the majority of diseases would be treated by the instantly claimed fusion protein.
Lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP § 2164.
See the decision in Rasmusson v. SmithKline 413 F.3d 1318, 1325 (Fed. Cir. 2005) which stated: “Thus, at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient. [Citation omitted.] ‘If mere plausibility were the test for enablement under §112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the “inventor” would be rewarded the spoils instead of the party who demonstrated that the method actually worked.’”
Therefore, in view of the Wands factors as discussed above, e.g., the amount of guidance provided, the predictability of the art and the lack of working examples, to practice the full scope of the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
No Double Patenting Rejections
An approved terminal disclaimer over application 18/823422, now U.S. Patent No. 12281148 was approved on 1/17/2025.
Pertinent Prior Art
Carmenate (doi: 10.4049/jimmunol.1201895) teaches a human IL-2 mutein that is effective in treating melanoma and lung carcinoma comprising the mutations R38A, F42A, Y45A, and E62A (abstract; pg 6232, col 1, para 1). Carmenate teaches mutating C125S for synthetic convenience and that mutating this residue did not appear to affect the biological activity of the mutein (pg 6232, col 1, para 1).
Allowable Subject Matter
Claims 1-3, 6-7, 8-11, 16, 17-23, 24-30, 35-39, and 42-44 are allowable.
Claims 1-33, 35-39, and 41-46 all contain allowable subject matter because they are drawn to a novel hIL-2 variant, a novel anti-PD1 antibody, or a combination of those two.
Claim 1, 8, 23-24
The modified hIL-2 described of claims 1, 8, and 23-24 was found allowable over the prior art. The closest prior art is that of Kang (US20210213102; SEQ ID NO: 36) who teaches a modified human IL-2 that is mutated at residues 62 and 64 (underlined below), but does not teach modifying human IL-2 at positions 3, 20, 38, or 125 as instantly claimed.
claim_1 AP*SSSTKKTQLQLEHLLLXLQMILNGINNYKNPKLTXMLTFKFYMPKKATELKHLQCLE 59
Kang_36 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLE 60
** **************** ***************** **********************
claim_1 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 119
Kang_36 ENLTPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
*:*.********************************************************
claim_1 WITF*QSIISTLT 131
Kang_36 WITFSQSIISTLT 133
**** ********
Claims 2-7, 9-16, 25-33, 35-39, 41-46
Dependent claims 2-7, 9-16, 25-33, 35-39, 41-46 which require the allowable hIL-2 variants are also rendered allowable over the prior art.
Dependent claims 9 and 11 are drawn to specific hIL-2 sequences that only include mutations at positions 20 and 38 as shown in the sequence alignment below, which were consequently found allowable over the prior art.
instant_345 APTSSSTKKTQLQLEHLLLXLQMILNGINNYKNPKLTXMLTFKFYMPKKATELKHLQCLE 60
instant_149 APTSSSTKKTQLQLEHLLLALQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_307 APTSSSTKKTQLQLEHLLLSLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_607 APTSSSTKKTQLQLEHLLLNLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_608 APTSSSTKKTQLQLEHLLLQLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_609 APTSSSTKKTQLQLEHLLLELQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_610 APTSSSTKKTQLQLEHLLLGLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_611 APTSSSTKKTQLQLEHLLLILQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_614 APTSSSTKKTQLQLEHLLLMLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_617 APTSSSTKKTQLQLEHLLLTLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
instant_620 APTSSSTKKTQLQLEHLLLVLQMILNGINNYKNPKLTEMLTFKFYMPKKATELKHLQCLE 60
******************* ***************** **********************
instant_345 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_149 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_307 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_607 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_608 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_609 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_610 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_611 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_614 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_617 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
instant_620 EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR 120
************************************************************
instant_345 WITFCQSIISTLT 133
instant_149 WITFCQSIISTLT 133
instant_307 WITFCQSIISTLT 133
instant_607 WITFCQSIISTLT 133
instant_608 WITFCQSIISTLT 133
instant_609 WITFCQSIISTLT 133
instant_610 WITFCQSIISTLT 133
instant_611 WITFCQSIISTLT 133
instant_614 WITFCQSIISTLT 133
instant_617 WITFCQSIISTLT 133
instant_620 WITFCQSIISTLT 133
*************
Dependent claims 14-15, and 33, drawn to SEQ ID NOs: 215-219 comprising additional mutations at positions 3 and/or 38 were also found allowable over the prior art.
Claim 17, 24
Claims 17 is drawn to specific anti-PD1 antibodies comprising the complete set of six CDRs described in claim 17. Claim 24 is drawn to a fusion protein comprising the same anti-PD1 antibodies as described in claim 17. These CDRs were not found in the prior art. It is understood in the art that changes to CDRs are unpredictable, thus there was no guidance to arrive at the specific CDR’s recited, given the art of record. Furthermore, it is known that antibody binding is defined by the structure of the six CDRs, thus is sufficient to convey possession of the invention.
Claim 18, 35
Claims 18 and 35 are drawn to an anti-PD1 antibody or immunoconjugate comprising an anti-PD1 antibody comprising the VH domain of SEQ ID NO: 416 and the VL domain of SEQ ID NO: 417, comprising the set of 6 CDRs described in claim 1. Neither of which was found in the prior art. The closest prior art to the VH domain is that of Rosenthal et al. (US20220185899, SEQ ID NO: 398), shown below. The CDRs have been underlined.
instant_416 EVQLLESGGGLVQPGGSLRLSCAASGFTFKSYAMHWVRQAPGKGLEWVSAIVYSGGSTYY 60
Rosenthal_398 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
*****************************.**** **************** *******
instant_416 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYDR---ASYFYDAMDVWGQGTT 117
Rosenthal_398 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVGGMYDGGVYYYGMDVWGQGTT 120
************************************** . .. :* .*********
instant_416 VTVSS 122
Rosenthal_398 VTVSS 125
*****
The closet prior art to the VL domain is that of Rosenthal’s SEQ ID NO: 379). The CDRs have been underlined.
instant_417 EIVLTQSPGTLSLSPGERATLSCRASQSISSSFLAWYQQKPGQAPRLLIYDASDRATGIP 60
Rosenthal_379 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYGASSRATGIP 60
****************************:*********************.**.******
instant_417 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYYDWPPLSFGGGTKVEIK 109
Rosenthal_379 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQY-GSPPLTFGGGTKVEIK 108
******************************** . ***:**********
Claim 37 is drawn to substitutions in the constant region, thus does not affect the allowability of the anti-PD1 antibody VH and VL regions.
Claims 18-23, 25-33, 35-39, 41, 45, 46
Dependent claims 18-23 and 25-33, 35-39, 41, 45, and 46 which require the novel sets of CDRs mentioned above are thus also rendered allowable over the prior art.
Conclusion
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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