DETAILED ACTION
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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed 07/06/2026 has been considered and the references therein are of record.
Response to Amendment
Applicant’s amendment filed 07/28/2026 is acknowledged. Claims 1-93 have been cancelled.
Claim 94 is amended. Claims 95-98 are new. Claims 94-98 are under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Objections Withdrawn
The objection to claim 8 for minor informalities is withdrawn in response to Applicant’s cancellation of the claim.
Rejections Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 54, 56, 62, 66-67, 71, and 94 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s cancelation of the claims, and Applicant’s amendment to claim 94 that removes the indefinite language of “at least about 80% sequence identity”.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 1-2, 7-8, 47-48, 53-56, 58-60, 62, 64, 66-67, 69, 71, 73-74, and 94 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in response to Applicant’s cancelation of the claims, and Applicant’s amendment to claim 94 that selects species illustrated in Figure 1 with 100% sequence identity to those in the Sequence Listing.
The rejection of claims 1-2, 7-8, 47-48, 53-56, 58-59, 60, 62, 64, 66-67, 69, 71, 73-74, and 94 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is withdrawn in response to Applicant’s cancelation of the claims, and Applicant’s amendment to claim 94 that removes “at least about 80% sequence identity” and that selects species illustrated in Figure 1 with 100% sequence identity to those in the Sequence Listing.
Claim Rejections - 35 USC § 103
The rejection of claims 1-2, 7-8, 47-48, 53-56, 58-59, 60, 62, 64, 66-67, 69, 71, 73-74 under 35 U.S.C. 103 is withdrawn in response to Applicant’s cancelation of the claims.
Rejections Maintained
This is a modified rejection necessitated by Applicant’s amendment to the claims.
Claim Rejections - 35 USC § 103
The rejection of claim 94 under 35 U.S.C. 103 as being unpatentable over Momin et al., 2019, in view of Flies et al., 2018 (WO2018027039A1), and further in view of Mumper et al., 2002 (US20020058795A1), Mingala et al., 2006, UniProt, 2006, Xie et al., 2003 (US20030166512A1) and Wittrup et al., 2017 (US20170216402A1) is maintained in response to Applicant’s amendment, which incorporated limitations of the cancelled claims into claim 94. This rejection is extended to new claims 95-96.
The instant claims are drawn to an immunomodulatory fusion protein (IFP) comprising:(i) an IL-2 comprising the amino acid sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2;(ii) an IL-12 comprising the amino acid sequence as set forth in SEQ ID NO: 5 or SEQ IDNO: 6.;(iii) a LAIR2 collagen-binding domain, wherein LAIR2 collagen-binding domain, comprises at least 80% identity to the amino acid sequence as set forth in SEQ ID NO: 15; and(iv) an albumin; wherein the albumin comprises at least about 80% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 16, 17, or[[-]] 182 wherein the LAIR2 collagen-binding domain and albumin are operably linked to each other and are positioned in between the IL-12 and the IL-2. The instant claims are drawn the immunomodulatory fusion protein having a molecular weight of about 100 to about 1000 kDa. The instant claims are drawn a pharmaceutical composition comprising the immunomodulatory fusion protein and a pharmaceutically acceptable carrier.
Momin teaches a linear immunomodulatory fusion protein (IFP) comprising murine Lumican (Supp. Materials and Methods) operably linked to murine serum albumin (MSA), murine IL2, or murine IL12, such as (from N-terminus to C-terminus) IL-12-MSA-Lumican, Lumican-MSA-IL-2, MSA-IL2, IL12-MSA, and Lumican-MSA (Results; Supp. Materials and Methods). Momin teaches the IL-12 at both the N-terminus and at the C-terminus (Table S1). Momin teaches the IL-2 at both the N-terminus and at the C-terminus (Table S1). Momin teaches the lumican domain of the IFP “binds collagen and demonstrates prolonged retention and systemic isolation after intratumoral injection” (see p. 2, Fig. 1). Momin teaches anchoring the IL-12 to collagen within the tumor using the collagen binding domain results in higher localized concentration of cytokine activity and reduces systemic toxicity (see p. 5, Fig. 3). Momin teaches that monotherapy with either IL-12-MSA-Lumican or Lumican-MSA-IL-2 treats cancer (see p. 4, Fig. 2 & p. 5, Fig. 3) and that coadministration of “IL12-MSA-Lumican plus Lumican-MSA-IL2 cures B16F10 tumors without systemic toxicity” (see p. 6, paragraph bridging left and right columns; p. 7, Fig. 4; & p. 9, Fig. 5). Momin teaches that “lumican is amenable to fusion to other immunomodulatory payloads and translation to several solid tumors” (see p. 9, right column, 2nd paragraph). Momin teaches the fusion protein in a pharmaceutically acceptable carrier (see p. 11, left column, last paragraph). Momin teaches that Lumican-MSA has a molecular weight (MW) of 104 kDA and that IL-2 has an MW of 16 kDa and IL-12 has an MW of 57 kDA (see p. 2, right column; p. 8, right column, 2nd paragraph).
Momin does not explicitly teach a composition comprising IL-2, a LAIR2 collagen-binding domain, an albumin, and IL-12, wherein the LAIR2 collagen-binding domain and albumin are operably linked to each other and are positioned in between the IL-12 and the IL-2. Momin does not teach SEQ ID NOs: 1-2, 5-6, or 15-18.
As Momin teaches anchoring cytokines to tumor collagen using collagen-binding domains, an ordinary artisan would be motivated to look for alternative collagen-binding domain options in the pursuit of optimizing the composition.
Flies teaches an immunomodulatory fusion protein comprising a LAIR2 collagen-binding domain (abstract; claims) which can be co-administered with cytokines to enhance the function of the fusion protein (V. Combination Therapies).
First, it would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Momin. One with ordinary skill in the art would be motivated to make and use the claimed invention because Momin teaches that combinational therapy of the two immunomodulatory fusion proteins, IL12-MSA-Lumican plus Lumican-MSA-IL2, act synergistically to treat cancer and that they are both useful and equivalents for the same purpose. Therefore, an ordinary artisan would have found it logical and obvious to make and use the claimed invention as Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements/compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Nevertheless, an ordinary artisan would have been motivated to fuse the two fusion proteins into one, creating a fusion protein that comprises IL12, MSA, Lumican, and IL2, since together they treat cancer better than either composition does alone. Moreover, an ordinary artisan would be motivated to make various constructions of this fusion protein, with the constituents in various arrangements, to optimize the efficacy of the fusion protein. Since Momin teaches that the IL12 and the IL2 at the termini of the peptide, it would be logical and obvious to simply construct the fusion protein of IL12-MSA-Lumican plus Lumican-MSA-IL2 into IL12-MSA-Lumican-IL2, IL12-Lumican-MSA-IL2, IL2-MSA-Lumican-IL12, and IL2-Lumican-MSA-IL12, where the cytokines are at the termini and the Lumican and MSA are between the cytokines, because Momin already teaches the cytokines at the termini of the fusion protein makes an effective composition.
Second, it would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Momin and Flies. One with ordinary skill in the art would be motivated to make and use the claimed invention because Flies teaches that LAIR2 is useful for the same purpose as lumican in an IFP, which is the purpose of binding collagen to anchor a fusion protein to a specific tissue. An ordinary artisan would find it obvious to try using an alternative collagen binding domains in the composition in the pursuit of optimizing the composition’s anti-tumor function. Furthermore, the person of ordinary skill in the art could have reasonably expected success because an ordinary artisan would readily recognize from the teachings of Momin and Flies that LAIR2 and Lumican are functional equivalents for the same purpose of binding collagen and are therefore interchangeable within the fusion protein.
Neither Momin or Flies teaches SEQ ID NOs: 1-2, 5-6, or 15-18. Mumper, Mingala, Rosen, St. Croix, Xie, and Wittrup remedy this deficiency by teaching sequences that an ordinary artisan would understand to be useful to make the claimed composition.
Mumper teaches a human IL-2 in Mumper SEQ ID NO: 3 (Db) that has 100% sequence identity to instant SEQ ID NO: 1 (Qy), as shown below.
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Mingala teaches an IL-12 subunit p40 (Db) that has 100% sequence identity to instant SEQ ID NO: 5 (Qy), as shown below.
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UniProt teaches a LAIR2 (Db) that has 100% sequence identity to instant SEQ ID NO: 15 (Qy), as shown below.
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Xie teaches a human albumin binding domain in Xie SEQ ID NO: 23(Db) that has 100% sequence identity to instant SEQ ID NO: 16 (Qy), as shown below.
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Wittrup teaches a human albumin binding domain in Wittrup SEQ ID NO: 36 (Db) that has 97.9% sequence identity to instant SEQ ID NO: 17 (Qy), as shown below.
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Wittrup teaches a human albumin binding domain in Wittrup SEQ ID NO: 36 (Db) that has 100% sequence identity to instant SEQ ID NO: 18 (Qy), as shown below.
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It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Momin, Flies, Mumper, Mingala, UniProt, Xie, and Wittrup. One with ordinary skill in the art would be motivated to make and use the claimed invention because, in the pursuit of making the immunomodulatory fusion protein that could be used to treat a human patient, an ordinary artisan would look to the prior art for known human sequences, or sequences that could be useful in a composition meant for humans, and would find sequences for each of the domains of the fusion protein in the disclosures of Mumper, Mingala, UniProt, Xie, and Wittrup. An ordinary artisan would find it obvious that there are many known sequence variations of each domain from which they could pick and choose as they attempted to make the most effective version of the immunomodulatory fusion protein, and as such would have a reasonably expected success in this pursuit. In regard to the human albumin binding domain taught by Wittrup, although it does not have 100% sequence identity to SEQ ID NO: 17, there is no evidence that the claimed sequence differs substantially enough to alter the structure in a way that alters its function. Therefore, an ordinary artisan would be motivated to combine the sequences taught by the prior art references to obtain the claimed IFP that is obvious in view of Momin and Flies. Thus, the claims are obvious in view of the prior art.
Response to Arguments
Applicant argues that the cited references fail to teach or suggest the amended claim 94 and that the rejection does not identify any teaching or suggestion of a fusion architecture in which LAIR2 and albumin are operably linked to one another as an intermediate module positioned between IL-12 and IL-2. Applicant argues that the cited references therefore do not disclose, nor provide any reason to arrive at, the specific structural arrangement now required by the claims. Applicant argues that, even assuming that a person of ordinary skill in the art would have been motivated to combine known cytokines, collagen-binding domains (CBD), and albumin-based spacers, the Office Action does not explain why such a person would have specifically selected an arrangement in which both LAIR2 and albumin are located between the IL-12 and IL-2 domains and operably linked to one another. Applicant argues that the prior art merely identifies individual components that could potentially be incorporated into fusion proteins, and does not provide a teaching that the LAIR2 domain and albumin spacer should be associated together within the interior of a bifunctional IL-12/IL-2 fusion construct. Moreover, Applicant argues that the Specification demonstrates that placement of the albumin spacer materially affects construct properties and cannot be regarded as an arbitrary design choice. Applicant argues that comparative construct studies described in FIGS. 2A-2F and FIG. 3 show that changes in domain arrangement resulted in substantially different product quality and expression yields. Applicant argues that these comparative results establish that domain placement is a critical structural variable. Applicant argues that the data show that alternative arrangements are not functionally equivalent and that modifying the position of albumin relative to the collagen-binding domain materially affects manufacturability and product quality. Applicant argues that the claimed arrangement of an operably linked LAIR2/albumin module between IL-12 and IL-2 cannot be dismissed as a routine optimization or predictable variation of prior-art fusion proteins. Applicant argues that the Specification further teaches that the disclosed collagen-localized bifunctional fusion proteins retain collagen binding while maintaining IL-12 and IL-2 biological activity and exhibit favorable antitumor properties. Applicant argues that the reported results demonstrate that successful integration of these functionalities within a single construct was not predictable. Applicant argues that a person of ordinary skill in the art therefore would not have had a reasonable expectation that simply combining known IL-12, IL-2, LAIR2, and albumin elements in an arbitrary arrangement would yield a construct possessing the advantageous properties reported in the present application. Applicant argues that the rejection is based on impermissible hindsight. Applicant argues that only after reading Applicant's disclosure could one selectively extract LAIR2 from one reference, albumin from another reference, cytokines from additional references, and then assemble them into the claimed configuration in which LAIR2 and albumin are operably linked and positioned between IL-12 and IL-2. Applicant argues that the cited art provides neither the necessary motivation nor a reasonable expectation of success for making this specific structural arrangement. Applicant argues that therefore amended claim 94 and new claims 95-98 are not obvious.
This has been fully considered, but is not found persuasive. In regards to Applicant’s argument that the prior art does not teach, suggest, or provide any reason to arrive at the structural arrangement of the fusion protein specified in amended claim 94, an ordinary artisan would have found it obvious in view of Momin and Flies, as discussed above, to arrive at the structural arrangement of the fusion protein because Flies teaches LAIR2 is functionally equivalent to Lumican and Momin teaches the cytokines are at the termini of the peptides and the CBD and albumin are operably linked, such that it would be obvious to combine the IL12-MSA-Lumican and Lumican-MSA-IL2 into one peptide where the cytokines are at the termini and where the CBD and albumin are operably linked and located between the cytokines. Moreover regarding Applicant’s argument that the prior art does not teach that the LAIR2 domain and albumin spacer should be associated together within the interior of a bifunctional IL-12/IL-2 fusion construct, an ordinary artisan would find it obvious from the constructs of IL12-MSA-Lumican and Lumican-MSA-IL2 that they could be effectively merged into one peptide where the architecture of the cytokines at the termini is maintained and where the CBD and albumin are linked together, producing IL12-Albumin-CBD-IL2, IL12- CBD-Albumin-IL2, IL2- Albumin- CBD-IL12, and IL2-CBD-Albumin-IL12, which maintains the architecture that was found to be efficacious by Momin. In regard to the Applicant’s argument that the specific structural arrangement is critical for product quality, expression yields, manufacturability, and functionality, it would be obvious to an ordinary artisan to construct the peptide so the CBD and albumin are linked together and between the cytokines for the reasons listed above, but even if it was not obvious, an ordinary artisan would find it obvious and routine to make and test various arrangements of IL-12, albumin, the CBD LAIR2, and IL-2 to find the arrangement that produces optimal product quality, expression yields, manufacturability, and functionality. In other words, it would be obvious and routine to an ordinary artisan to arrive at the specific arrangement because Momin already teaches effective arrangements where the cytokines are located at the termini and where the albumin and CBD are fused together and because an ordinary artisan would want to ensure the domains are in the optimal arrangement. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
New Rejections
The new rejections are necessitated by Applicant’s amendment to the claims.
Claim Rejections - 35 USC § 103
Claim 97-98 are rejected under 35 U.S.C. 103 as being unpatentable over Momin et al., 2019, in view of Flies et al., 2018 (WO2018027039A1), and further in view of Cheung et al., 2019 (WO2020086758A1), Gao et al., 2011 (CN102174479A), UniProt, 2006, Balance et al., 2003 (US20030199043A1), and Austin et al., 2002 (US20020041865A1).
The instant claims are drawn to an immunomodulatory fusion protein comprising the amino acid sequence as set forth in SEQ ID NO: 45. The instant claims are drawn to a pharmaceutical composition comprising the immunomodulatory fusion protein, and a pharmaceutically acceptable carrier.
Importantly, the specification states in Table 6 that SEQ ID NO: 45 comprises IL12-LAIR2-HAS(human serum albumin)-IL2 with “normal linkers”.
The teachings of Momin and Flies are discussed above in the preceding rejection and are hereby incorporated. Momin further teaches that the domains of the fusion protein are linked via GGSGGGSGGGSGGGS, GGGSGGGS, and GGGS (Table S1). Momin further teaches that a His-Tag, such as an HHHHHH His-Tag, at the C-terminus of the fusion protein (Table S1).
Neither Momin nor Flies explicitly teach a IFP with SEQ ID NO: 45.
Cheung, Gao, UniProt, Balance, and Austin remedy this deficiency by teaching sequences that an ordinary artisan would understand to be useful to make the claimed composition.
Cheung teaches a p40 subunit of human IL-12 within a fusion protein in Cheung SEQ ID NO: 292 (Db) that has 99.2% sequence identity to the IL-12 domain (spanning from position 1 to position 327) within SEQ ID NO:45, as shown below.
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Gao teaches a p35 subunit of human IL-12 in Gao SEQ ID NO:1 (Db) that has 100% sequence identity to the IL-12 domain (spanning from position 343 to position 539) within SEQ ID NO:45, as shown below.
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UniProt teaches a LAIR2 (Db) that has 100% sequence identity to the LAIR2 domain (spanning from position 549 to position 679) within SEQ ID NO:45, as shown below.
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Ballance 2003 US20030199043A1 teaches an HSA (Db) in Ballance SEQ ID NO: 18 that has 100% sequence identity to the HSA domain (spanning from position 689 to position 1273) within SEQ ID NO:45, as shown below.
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Austin teaches an human IL-2 (Db) in Austin SEQ ID NO: 8 that has 100% sequence identity to the IL-2 domain (from position 1283 to position 1415) within SEQ ID NO:45, as shown below.
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It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Momin, Flies, Cheung, Gao, UniProt, Balance, and Austin. One with ordinary skill in the art would be motivated to make and use the claimed invention because, in the pursuit of making the immunomodulatory fusion protein that could be used to treat a human patient, an ordinary artisan would look to the prior art for known human sequences, or sequences that could be useful in a composition meant for humans, and would find sequences for each of the domains of the fusion protein in the disclosures of Cheung, Gao, UniProt, Balance, and Austin. An ordinary artisan would find it obvious that there are many known sequence variations of each domain from which they could pick and choose as they attempted to make the most effective version of the immunomodulatory fusion protein, and as such would have a reasonably expected success in this pursuit. In regard to the human IL-12 taught by Cheung, although it does not have 100% sequence identity to the IL-12 domain within SEQ ID NO: 45, there is no evidence that the claimed sequence differs substantially enough to alter the structure in a way that alters its function. Therefore, an ordinary artisan would be motivated to combine the sequences taught by the prior art references to obtain the claimed IFP that is obvious in view of Momin and Flies. Thus, the claims are obvious in view of the prior art.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH CESARE whose telephone number is (571)272-6908. The examiner can normally be reached Monday - Friday 10am-4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (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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/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
