DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant’s election of invention: Group I (claims 59-74) and species: IL-12 combined with PD-L2 (claims 59-64 and 68-74) in the reply filed on February 13, 2026 is acknowledged. Claims 59-78 are presently pending. Claims 65-67 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 13, 2026.
Objection to the Specification
3. There are trademarks in this application that do not meet the requirements.
The use of the term e.g., BLAST and DNASTAR at para. [0089], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correction is required.
Claim Rejections - 35 USC § 112
4. 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.
Written Description
5. Claims 59-64 and 68-74 are rejected 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. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The claims are directed to immunomodulatory molecules comprising features: agonists of inhibitory checkpoint molecules; immunostimulatory cytokines; hinge regions; and Fc domains. The claims include “variants” and “portions” of the agonists, cytokines, and Fc domains, and many potential configurations of the features. For example, instant claim 71 claims 11 different configurations for the immunomodulatory molecule—and many more once “optional” features are accounted for.
The claimed immunomodulatory molecules must possess specific functions, including recognizing target molecules and up-regulating / down-regulating immune response. There is no structure presented that would correlate with these functions. The specification only sets forth three IL-12 paired with PD-L2 fusion constructs specifically as potentially having the required functions, but these three species are not sufficiently representative of such a broad genus of immunomodulatory molecules as instantly claimed.
A. No Written Description for “Variants” or “Portions” of the Claim-Recited Features
The claimed invention recites “variants” and “portions” of the claim-recited agonist, cytokine, and Fc domain features, and the broadest reasonable interpretation for this recitation is: the claim language reads on immunomodulatory molecules comprising fragments of the features. However, the specification only demonstrates immunomodulatory molecules having specific amino acid substation “variants;” no immunomodulatory molecules comprising “portions” or fragments of the features are demonstrated.
With regards to the elected species (IL-12 paired with PD-L2), the specification discloses immunomodulatory properties of only three constructs: IW-#29, IW #30, and IW #34 at FIGs. 2A-C, 3A-B, 4A-B, 5A-C, 6A-B, 7A-B, 8A-C, 9A-C, 16, 17, 18, and 19.
IW-#29 (IL-12(E59A/F60A)/PD-L2-Fc) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 17 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-single chain IL-12(E59A/F60A) variant (SEQ ID NO: 68)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)); and one pairing polypeptide comprising SEQ ID NO: 16 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)).
IW-#30 (IL-12(F60A)/PD-L2-Fc) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 18 or 142 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-single chain IL-12(F60A) variant (SEQ ID NO: 71)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)); and one pairing polypeptide comprising SEQ ID NO: 16 or 115 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)).
IW-#34 (PD-L2-Fc/IL-12(F60A)) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 20 or 143 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)-GGGGSGGGGSGGGGS linker (SEQ ID NO: 229)-single chain IL-12(F60A) variant (SEQ ID NO: 71)); and one pairing polypeptide comprising SEQ ID NO: 16 or 115 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)). See instant specification at para. [0627].
The specification therefore only demonstrates constructs having a single Fc sequence, a single PD-L2 sequence, and two IL-12 variant sequences (E59A/F60A or F60A). No specific fragments of these features are demonstrated in the specification. However, the specification teaches at paragraph [0193]:
A “cytokine variant” herein refers to any cytokine molecule that is not naturally existing, such as a cytokine active fragment (e.g., a cytokine fragment that retains at least about 10% biological activity or cytokine receptor binding activity of a full-length cytokine), a mutant, or a derivative thereof.
This teaching suggests that many immunomodulatory molecules having various fragments of claim-recited features are encompassed by the claims, but the specification does not define any structural features commonly possessed by members of the genus. The claims recite functional language of the immunomodulatory molecules, such as “recognizing” a target molecule and “regulating” an immune response, however a definition by function does not suffice to define the genus because it is only an indication of what the immunomodulatory molecule does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of immunomodulatory molecules is highly variable (i.e., each molecule comprising a fragment of a feature would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed immunomodulatory molecules having fragments of the claim-recited features have no correlation between their structure and function.
To address this issue, a brief assessment of the state of the art regarding fragments of amino acid sequence is made herein, showing that it is unpredictable how a fragment of a short amino acid sequence will function, let alone fragments of longer amino sequences comprising domains of fusion proteins:
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence had substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible immunomodulatory molecules comprising fragments of features as instantly claimed. Therefore, neither the art nor the specification provides a sufficient representative number of immunomodulatory molecules comprising fragments of agonists, cytokines, and Fc domains to meet the written description requirement for instant claims encompassing immunomodulatory molecules having fragments of these features.
It is therefore unknown how the genus of immunomodulatory molecules comprising fragments of agonists, cytokines, and Fc domains would recognize target molecules and regulate immune response. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of immunomodulator molecules comprising fragments of agonists, cytokines, and Fc domains encompassed by the claims. Given all of the above, Applicant does not have written description for “variants” or “portions” of agonists, cytokines, and Fc domains.
B. No Written Description for the Breath of the Claims
Claims 59-64, 68-70, and 74 are very broad and fail to recite additional necessary features of the immunomodulatory molecules, such as hinge regions and Fc domains; and claims 71-73 recite various configurations of the agonists, cytokines, hinge, and Fc domain features of the immunomodulatory molecules. Additional necessary features of the immunomodulatory molecules, such as specific linkers, are wholly omitted from the claims.
As shown above, the specification only provides examples of (i) two specific configurations of immunomodulatory molecules and (ii) two IL-12 variants. The specification also shows that the construct must be paired with a second construct, however this is only claimed in claims 71 and 72. Additionally, the instant specification discusses the importance of a “restricted activation mechanism” for the immunomodulatory molecule at para. [0021]:
[instant immunomodulatory molecules] can further have a “restricted activation mechanism”, in which the first binding domain upon binding to an immune cell upregulating an immune response (e.g., immunostimulatory cytokine, such as IL-12 or IL-2) is modified to reduce activity (binding and/or biological activity), and/or in a “masked” configuration (e.g., positioned at hinge region) until binding of the second binding domain to the second target antigen (e.g., tumor antigen, or immune cell surface molecule) occurs.
It is apparent that each of three constructs demonstrated in the specification (i.e., IW-#29, IW #30, and IW #34) not only has IL-12 mutations to reduce activity of the IL-12, but also places the IL-12 or PD-L2 proximal to a hinge domain, in a “masked” configuration. However, the claims recite configurations wholly lacking hinge domains, let alone placing the IL-12 or PD-L2 in the correct location relative to the hinge domain to effectuate “masking.”
Therefore, the breadth of the claims encompasses a broad genus of immunomodulatory molecules with unknown functionality. To address this issue, a brief assessment of the state of the art regarding unpredictability in fusion protein design is made herein.
Wu et al. ("A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies." Cell Reports Medicine 5.10 (2024)) is directed to a PD1-IL2R-IL2 fusion protein, which attenuates systemic IL-2 activity and toxicity by masking the IL2. Wu et al.at summary. Wu et al. shows that there is little predictability in how well a fusion protein will work, as choice of masking domain and configuration of IL2, Fc domain, and masking domain resulted in over a 100-fold effect on fusion protein activity. See Wu et al.at FIGs. S2D-E. Wu et al.further shows that choice of linkers between the IL2, Fc domain, and masking domain had a lesser, but still significant effect on fusion protein activity. See Wu et al.at FIGs. S2G.
Silacci et al. ("Linker length matters, fynomer-Fc fusion with an optimized linker displaying picomolar IL-17A inhibition potency." Journal of Biological Chemistry 289.20 (2014): 14392-14398) is directed to Fynomer-Fc fusion proteins for inhibiting IL-17A. Silacci et al. at title. In this instance, the linker length “influenced significantly the potency of [the] Fc fusion proteins.” Silacci et al. at conclusion.
Chen et al. ("Fusion protein linkers: property, design and functionality." Advanced drug delivery reviews 65.10 (2013): 1357-1369) is a review of linkers in fusion protein design. Chen et al. teaches that “successful construction of a recombinant fusion protein requires two indispensable elements: the component proteins and the linkers. The choice of the component proteins is based on the desired functions of the fusion protein product and, in most cases, is relatively straightforward. On the other hand, the selection of a suitable linker to join the protein domains together can be complicated and is often neglected in the design of fusion proteins. Direct fusion of functional domains without a linker may lead to many undesirable outcomes, including misfolding of the fusion proteins, low yield in protein production, or impaired bioactivity. Therefore, the selection or rational design of a linker to join fusion protein do mains is an important, yet underexplored, area in recombinant fusion protein technology.” Chen et al. at introduction.
Challener ("Fusion proteins pose manufacturability challenges." BioPharm International 30.5 (2017): 30-31) is directed to challenges in fusion protein manufacturing. Challener at title. Challener teaches that “Achieving and maintaining proper folding for each of the components in fusion proteins is a major challenge in the molecular design of these products. Issues can arise when domains are taken out of their natural context, or a domain is combined with a second domain with which it does not fold well. As a result, combining the different components of the fusion protein that do not naturally occur together can lead to instability with the composite molecule, creating manufacturing challenges such as aggregation[.]” Challener at the need for stabilization. Therefore, “[a] key aspect of improving the manufacturability of fusion proteins lies with their design, which should be focused on minimizing the subsequent residual liabilities that remain for process development.” Challener at new design strategies.
Therefore, careful design of a fusion protein’s configuration—including the linkers used to fuse the various domains of the fusion protein—is critical to the functionality of the fusion protein, and also requires validation / experimentation to solve the well-known challenges associated with this technology. Accordingly, without actually performing the required experiments, it is unpredictable what species of the instantly claimed genus of immunomodulatory molecules are functional. Given all of the above, Applicant does not have written description for the genus of immunomodulatory molecules instantly claimed.
The cited references therefore demonstrate that Applicants are not in possession of the broad genus of immunomodulatory molecules instantly claimed.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
6. Claims 59-64 and 68-74 are 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 specific immunomodulatory molecules having the features of constructs IW-#29, IW #30, and IW #34, does not reasonably provide enablement for the broad genus of immunomodulatory molecules instantly claimed, e.g., having unspecified linkers, fragments of features of the molecule, and permutations of how the features are ordered within the molecule. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to immunomodulatory molecules comprising features: agonists of inhibitory checkpoint molecules; immunostimulatory cytokines; hinge regions; and Fc domains. The claims include “variants” and “portions”—i.e., fragments—of the agonists, cytokines, and Fc domains, and many potential configurations of the features. For example, instant claim 71 claims 11 different configurations for the immunomodulatory molecule—and many more once “optional” features are accounted for. The claimed immunomodulatory molecules must possess specific functions, including recognizing target molecules and up-regulating / down-regulating immune response. The claims are therefore broad, especially claims 59-64, 68-70, and 74 that require an agonists of inhibitory checkpoint molecules and an immunostimulatory cytokines, but not a hinge region or Fc domains.
(5) The predictability or unpredictability of the art:
A) The prior art indicates it is unpredictable whether an immunomodulatory molecule comprising fragments of the various features of the immunomodulatory molecule would still retain the ability to recognize a target molecule or regulate an immune response.
For example, Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence had substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible immunomodulatory molecules comprising fragments of features as instantly claimed.
The cited references therefore demonstrate that creating a functional immunomodulatory molecule comprising fragments of the various features is highly unpredictable, if even possible.
B) The prior art also indicates it is unpredictable which configurations of features in claim-recited immunomodulatory molecules would retain the ability to recognize a target molecule or regulate an immune response.
For example, Wu et al. ("A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies." Cell Reports Medicine 5.10 (2024)) is directed to a PD1-IL2R-IL2 fusion protein, which attenuates systemic IL-2 activity and toxicity by masking the IL2. Wu et al.at summary. Wu et al. shows that there is little predictability in how well a fusion protein will work, as choice of masking domain and configuration of IL2, Fc domain, and masking domain resulted in over a 100-fold effect on fusion protein activity. See Wu et al.at FIGs. S2D-E. Wu et al.further shows that choice of linkers between the IL2, Fc domain, and masking domain had a lesser, but still significant effect on fusion protein activity. See Wu et al.at FIGs. S2G.
Silacci et al. ("Linker length matters, fynomer-Fc fusion with an optimized linker displaying picomolar IL-17A inhibition potency." Journal of Biological Chemistry 289.20 (2014): 14392-14398) is directed to Fynomer-Fc fusion proteins for inhibiting IL-17A. Silacci et al. at title. In this instance, the linker length “influenced significantly the potency of [the] Fc fusion proteins.” Silacci et al. at conclusion.
Chen et al. ("Fusion protein linkers: property, design and functionality." Advanced drug delivery reviews 65.10 (2013): 1357-1369) is a review of linkers in fusion protein design. Chen et al. teaches that “successful construction of a recombinant fusion protein requires two indispensable elements: the component proteins and the linkers. The choice of the component proteins is based on the desired functions of the fusion protein product and, in most cases, is relatively straightforward. On the other hand, the selection of a suitable linker to join the protein domains together can be complicated and is often neglected in the design of fusion proteins. Direct fusion of functional domains without a linker may lead to many undesirable outcomes, including misfolding of the fusion proteins, low yield in protein production, or impaired bioactivity. Therefore, the selection or rational design of a linker to join fusion protein do mains is an important, yet underexplored, area in recombinant fusion protein technology.” Chen et al. at introduction.
Challener ("Fusion proteins pose manufacturability challenges." BioPharm International 30.5 (2017): 30-31) is directed to challenges in fusion protein manufacturing. Challener at title. Challener teaches that “Achieving and maintaining proper folding for each of the components in fusion proteins is a major challenge in the molecular design of these products. Issues can arise when domains are taken out of their natural context, or a domain is combined with a second domain with which it does not fold well. As a result, combining the different components of the fusion protein that do not naturally occur together can lead to instability with the composite molecule, creating manufacturing challenges such as aggregation[.]” Challener at the need for stabilization. Therefore, “[a] key aspect of improving the manufacturability of fusion proteins lies with their design, which should be focused on minimizing the subsequent residual liabilities that remain for process development.” Challener at new design strategies.
Therefore, the cited references indicate that careful design of a fusion protein’s configuration—including the linkers used to fuse the various domains of the fusion protein—is critical to the functionality of the fusion protein, and also requires validation / experimentation to solve the well-known challenges associated with this technology. Accordingly, without actually performing the required experiments, it is unpredictable what species of the instantly claimed genus of immunomodulatory molecules are functional.
6) the amount of direction or guidance provided by the inventor:
With regards to the elected species (IL-12 paired with PD-L2), the specification discloses immunomodulatory properties of only three constructs: IW-#29, IW #30, and IW #34 at FIGs. 2A-C, 3A-B, 4A-B, 5A-C, 6A-B, 7A-B, 8A-C, 9A-C, 16, 17, 18, and 19.
IW-#29 (IL-12(E59A/F60A)/PD-L2-Fc) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 17 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-single chain IL-12(E59A/F60A) variant (SEQ ID NO: 68)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)); and one pairing polypeptide comprising SEQ ID NO: 16 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)).
IW-#30 (IL-12(F60A)/PD-L2-Fc) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 18 or 142 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-single chain IL-12(F60A) variant (SEQ ID NO: 71)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)); and one pairing polypeptide comprising SEQ ID NO: 16 or 115 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)).
IW-#34 (PD-L2-Fc/IL-12(F60A)) comprises one IL-12 fusion polypeptide comprising SEQ ID NO: 20 or 143 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 88)-Fc domain subunit (SEQ ID NO: 97)-GGGGSGGGGSGGGGS linker (SEQ ID NO: 229)-single chain IL-12(F60A) variant (SEQ ID NO: 71)); and one pairing polypeptide comprising SEQ ID NO: 16 or 115 (from N′ to C′: PD-L2 extracellular domain (SEQ ID NO: 106)-GSG linker (SEQ ID NO: 203)-hinge (SEQ ID NO: 87)-Fc domain subunit (SEQ ID NO: 98)). See instant specification at para. [0627].
The specification therefore only demonstrates constructs having a single Fc sequence, a single PD-L2 sequence, a single hinge region sequence, two linker variants, and two IL-12 variant sequences (E59A/F60A or F60A)—notably, the specification therefore only demonstrates two distinct configurations of the claim-recited features, i.e., (i) IW-#29/30 and (ii) IW-# 34. It is therefore highly unpredictable what other feature variants / feature portions / feature fragments, and in what configuration, connected by unspecified linkers, will be functional.
8) the quantity of experimentation needed to make or use the invention:
Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings regarding immunomodulatory properties of IW-#29, IW-#30, and IW-# 34 to the broad genus of immunomodulatory molecules instantly claimed, without undue experimentation. It would undue experimentation to confirm which of the 1000s of immunomodulatory molecules encompassed by the claims successfully recognize the target molecules and regulate immune response.
In conclusion, the claimed invention does not provide enablement for the broad genus of immunomodulatory molecules instantly claimed. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
7. 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 71-73, 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.
a) Claims 71-73 are drawn to various configuration of immunomodulatory molecules having hinge regions, Fc domains, and binding domains. For example, claim 71 recites the first binding domain is “positioned at the hinge domain,” and claim 72 recites that subunits of IL-12 are “positioned in tandem at a first hinge region.” It is unclear if positioning “at” a hinge region includes positioning (i) before the hinge region, (ii) after the hinge region, and/or (iii) within the hinge region. Clarification and/or correction is required.
b) Claims 71-73 also recite “portions of” the various domains, e.g., Fc domain subunits and binding domains. It is unclear if “portion” includes any fragment of the domain, including as few as any two amino acids of the domain. Clarification and/or correction is required.
Claim Rejections - 35 USC § 102
8. 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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claims 59-61, 68-71, and 74 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Krupnick et al. (US 20190119345A1, published April 25, 2019).
Claim 59 is drawn to an immunomodulatory molecule comprising a first binding domain specifically recognizing a first target molecule and a second binding domain specifically recognizing a second target molecule, wherein the first binding domain upon binding to the first target molecule up-regulates an immune response, and wherein the second binding domain upon binding to the second target molecule down-regulates the immune response, wherein the first binding domain is an immunostimulatory cytokine or variant thereof, and the second binding domain is an agonist of an inhibitory checkpoint molecule.
Claim 60 is drawn to the immunomodulatory molecule of claim 59, wherein the immunostimulatory cytokine or variant thereof is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-12, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-27, TFN-a, IFN-b, IFN-y, TNF-a, erythropoietin, thrombopoietin, G-CSF, M-CSF, SCF, and GM-CSF.
Claim 61 is drawn to the immunomodulatory molecule of claim 60, wherein the immunostimulatory cytokine or variant thereof is IL-12 or variant thereof.
Claim 68 is drawn to the immunomodulatory molecule of claim 59, wherein the inhibitory checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, HHLA2, CD47, CXCR4, CD160, CD73, BLTA, B7-H4, TIGIT, Siglec7, Siglec9, and VISTA.
Claim 69 is drawn to the immunomodulatory molecule of claim 59, wherein the agonist of the inhibitory checkpoint molecule is a ligand or an antibody or antigen-binding fragment thereof.
Claim 70 is drawn to the immunomodulatory molecule of claim 69, (i) wherein the inhibitory checkpoint molecule is PD-1, and wherein the agonist of the inhibitory checkpoint molecule is PD-L1, PD-L2, or a variant thereof; (ii) wherein the inhibitory checkpoint molecule is TIGIT, and wherein the agonist of the inhibitory checkpoint molecule is CD 112, CD 155, or a variant thereof; (iii) wherein the inhibitory checkpoint molecule is LAG-3, and wherein the agonist of the inhibitory checkpoint molecule is MHC II, LSECtin, or a variant thereof; (iv) wherein the inhibitory checkpoint molecule is TIM-3, and wherein the agonist of the inhibitory checkpoint molecule is Galectin-9, Caecam-1, HMGB-1, phosphatidylserine, or a variant thereof; or (v) wherein the inhibitory checkpoint molecule is CTLA-4, and wherein the agonist of the inhibitory checkpoint molecule is CD80, CD86, or a variant thereof.
Claim 71 is drawn to the immunomodulatory molecule of claim 59, wherein the immunomodulatory molecule comprises: (i) an antigen-binding polypeptide comprising from N-terminus to C-terminus: the second binding domain or portion thereof, a hinge region, and an Fc domain subunit or a portion thereof, and wherein the first binding domain is positioned at the hinge region; (ii) an antigen-binding polypeptide comprising from N' to C': the first binding domain or portion thereof, the second binding domain or portion thereof, an optional hinge region, and an Fc domain subunit or a portion thereof; (iii) an antigen-binding polypeptide from N-terminus to C-terminus: the second binding domain or portion thereof, an optional hinge region, an Fc domain subunit or a portion thereof, and the first binding domain or portion thereof; (iv) an antigen-binding polypeptide comprising from N-terminus to C-terminus: the first binding domain or portion thereof, an optional hinge region, an Fc domain subunit or a portion thereof, and the second binding domain or portion thereof.
Claim 74 is drawn to a pharmaceutical composition comprising the immunomodulatory molecule of claim 59, and optionally a pharmaceutical acceptable carrier.
Krupnick et al. is directed to immunomodulatory molecules for targeted cytokine delivery. Krupnick et al. at abstract. Krupnick et al. teaches PD-L2 / cytokine fusion proteins, i.e., an agonist of inhibitory checkpoint molecule (PD-L2 is ligand/agonist specifically recognizing PD-1 inhibitory checkpoint molecule) fused to immunostimulatory cytokine specifically recognizing a different target molecule. Krupnick et at. at FIG. 36. Krupnick et al. teaches the cytokine may be IL-12. Krupnick et al. at para. [0079]. Although Krupnick et al. does not explicitly teach that the immunostimulatory cytokine “up-regulates an immune response” and that the agonist of the inhibitory checkpoint molecule “down regulates the immune response,” the recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See e.g., MPEP sections 2111.02, 2112. That is the case here since fusion protein of Krupnick et al. was inherently capable of regulating the immune response, as demonstrated by the instant specification (claims 59-61, 68-70).
Regarding claims 71 and 74, Krupnick et al. also teaches the fusion protein may further comprise a Fc domain subunit (see e.g., Krupnick et al. at para. [0061, last sentence]; claim 71); and that the fusion protein may be comprised in a pharmaceutical composition (see e.g., Krupnick et al. at para. [0019]; claim 74). Krupnick et al. therefore anticipates claims 59-61, 68-71 and 74.
Claim Rejections - 35 USC § 103
10. 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.
11. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claims 59-64, 68-71, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Krupnick et al. in view of Garcia et al. (WO 2021/212083 A2, published October 21, 2021; US 17/995,986 is the respective US national phase application).
Claim 59 is drawn to an immunomodulatory molecule comprising a first binding domain specifically recognizing a first target molecule and a second binding domain specifically recognizing a second target molecule, wherein the first binding domain upon binding to the first target molecule up-regulates an immune response, and wherein the second binding domain upon binding to the second target molecule down-regulates the immune response, wherein the first binding domain is an immunostimulatory cytokine or variant thereof, and the second binding domain is an agonist of an inhibitory checkpoint molecule.
Claim 60 is drawn to the immunomodulatory molecule of claim 59, wherein the immunostimulatory cytokine or variant thereof is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-12, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-27, TFN-a, IFN-b, IFN-y, TNF-a, erythropoietin, thrombopoietin, G-CSF, M-CSF, SCF, and GM-CSF.
Claim 61 is drawn to the immunomodulatory molecule of claim 60, wherein the immunostimulatory cytokine or variant thereof is IL-12 or variant thereof.
Claim 62 is drawn to the immunomodulatory molecule of claim 61, wherein the IL-12 variant comprises one or more mutations within the p40 subunit at a position selected from the group consisting of E45, Q56, V57, K58, E59, F60, G61, D62, A63, G64, Q65, and C177 relative to a wildtype p40 subunit.
Claim 63 is drawn to the immunomodulatory molecule of claim 62, wherein the IL-12 variant comprises an E59A mutation, an F60A mutation, an F60D mutation, or E59A/F60A mutations within the p40 subunit relative to wildtype p40 subunit.
Claim 64 is drawn to the immunomodulatory molecule of claim 63, wherein the p40 subunit of the IL-12 variant comprises the amino acid sequence of any of SEQ ID NOs: 63-66 and 140.
Claim 68 is drawn to the immunomodulatory molecule of claim 59, wherein the inhibitory checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-3, HHLA2, CD47, CXCR4, CD160, CD73, BLTA, B7-H4, TIGIT, Siglec7, Siglec9, and VISTA.
Claim 69 is drawn to the immunomodulatory molecule of claim 59, wherein the agonist of the inhibitory checkpoint molecule is a ligand or an antibody or antigen-binding fragment thereof.
Claim 70 is drawn to the immunomodulatory molecule of claim 69, (i) wherein the inhibitory checkpoint molecule is PD-1, and wherein the agonist of the inhibitory checkpoint molecule is PD-L1, PD-L2, or a variant thereof; (ii) wherein the inhibitory checkpoint molecule is TIGIT, and wherein the agonist of the inhibitory checkpoint molecule is CD 112, CD 155, or a variant thereof; (iii) wherein the inhibitory checkpoint molecule is LAG-3, and wherein the agonist of the inhibitory checkpoint molecule is MHC II, LSECtin, or a variant thereof; (iv) wherein the inhibitory checkpoint molecule is TIM-3, and wherein the agonist of the inhibitory checkpoint molecule is Galectin-9, Caecam-1, HMGB-1, phosphatidylserine, or a variant thereof; or (v) wherein the inhibitory checkpoint molecule is CTLA-4, and wherein the agonist of the inhibitory checkpoint molecule is CD80, CD86, or a variant thereof.
Claim 71 is drawn to the immunomodulatory molecule of claim 59, wherein the immunomodulatory molecule comprises: (i) an antigen-binding polypeptide comprising from N-terminus to C-terminus: the second binding domain or portion thereof, a hinge region, and an Fc domain subunit or a portion thereof, and wherein the first binding domain is positioned at the hinge region; (ii) an antigen-binding polypeptide comprising from N' to C': the first binding domain or portion thereof, the second binding domain or portion thereof, an optional hinge region, and an Fc domain subunit or a portion thereof; (iii) an antigen-binding polypeptide from N-terminus to C-terminus: the second binding domain or portion thereof, an optional hinge region, an Fc domain subunit or a portion thereof, and the first binding domain or portion thereof; (iv) an antigen-binding polypeptide comprising from N-terminus to C-terminus: the first binding domain or portion thereof, an optional hinge region, an Fc domain subunit or a portion thereof, and the second binding domain or portion thereof.
Claim 74 is drawn to a pharmaceutical composition comprising the immunomodulatory molecule of claim 59, and optionally a pharmaceutical acceptable carrier.
Krupnick et al. teaches PD-L2 / cytokine fusion proteins, i.e., an agonist of inhibitory checkpoint molecule (PD-L2 is ligand/agonist specifically recognizing PD-1 inhibitory checkpoint molecule) fused to immunostimulatory cytokine specifically recognizing a different target molecule. Krupnick et at. at FIG. 36. Krupnick et al. teaches the cytokine may be IL-2 or IL-12. Krupnick et al. at para. [0079]. Although Krupnick et al. does not explicitly teach that immunostimulatory cytokine “up-regulates an immune response” and that the agonist of the inhibitory checkpoint molecule “down regulates the immune response,” the recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See e.g., MPEP sections 2111.02, 2112. That is the case here since fusion protein of Krupnick et al. was inherently capable of regulating the immune response, as demonstrated by the instant specification (claims 59-61, 68-70). Krupnick et al. also teaches the fusion protein may further comprise a Fc domain subunit (see e.g., Krupnick et al. at para. [0061, last sentence]; claim 71); and that the fusion protein may be comprised in a pharmaceutical composition (see e.g., Krupnick et al. at para. [0019]; claim 74).
Krupnick et al. does not explicitly teach the IL-12 variants and sequences recited at instant claims 62-64.
Garcia et al. is directed to IL-12 variants for modulating signal transduction. Garcia et al. at abstract. SEQ ID NOs: 3, 4, and 13 of Garcia et al. disclose the instantly claimed E59A, F60A, and E59A/F60A IL-12 variants, and comprise the instantly claimed SEQ ID NOs: 64 (E59A), 65 (F60A), and 63 (E59A/F60A), respectively (claims 62-64). An alignment of the instantly claimed sequences to the sequences of Garcia et al. is provided below for Applicant’s convenience:
INSTANT SEQ ID NO:64 (IL-12 E59A) ALIGNED TO GARCIA ET AL. SEQ ID NO:3
TITLE OF INVENTION: Engineered IL-12 and IL-23 Polypeptides and Uses Thereof
PRIOR APPLICATION NUMBER: PCT/US2021/027838
PRIOR FILING DATE: 2020-04-16
NUMBER OF SEQ ID NOS: 27
SEQ ID NO 3
LENGTH: 328
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic construct
FEATURE:
NAME/KEY: MISC_FEATURE
OTHER INFORMATION: human IL-12p40 variant E81A
Query Match 100.0%; Score 1643; Length 328;
Best Local Similarity 100.0%;
Matches 306; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKAF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKAF 82
Qy 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 142
Qy 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 202
Qy 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 262
Qy 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 263 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 322
Qy 301 ASVPCS 306
||||||
Db 323 ASVPCS 328
INSTANT SEQ ID NO:65 (IL-12 F60A) ALIGNED TO GARCIA ET AL. SEQ ID NO:4
TITLE OF INVENTION: Engineered IL-12 and IL-23 Polypeptides and Uses Thereof
PRIOR APPLICATION NUMBER: PCT/US2021/027838
PRIOR FILING DATE: 2020-04-16
NUMBER OF SEQ ID NOS: 27
SEQ ID NO 4
LENGTH: 328
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic construct
FEATURE:
NAME/KEY: MISC_FEATURE
OTHER INFORMATION: human IL-12p40 variant F82A
Query Match 100.0%; Score 1642; Length 328;
Best Local Similarity 100.0%;
Matches 306; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEA 82
Qy 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 142
Qy 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 202
Qy 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 262
Qy 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 263 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 322
Qy 301 ASVPCS 306
||||||
Db 323 ASVPCS 328
INSTANT SEQ ID NO:63 (IL-12 E59A/F60A) ALIGNED TO GARCIA ET AL. SEQ ID NO:13
TITLE OF INVENTION: Engineered IL-12 and IL-23 Polypeptides and Uses Thereof
PRIOR APPLICATION NUMBER: PCT/US2021/027838
PRIOR FILING DATE: 2020-04-16
NUMBER OF SEQ ID NOS: 27
SEQ ID NO 13
LENGTH: 328
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic construct
FEATURE:
NAME/KEY: MISC_FEATURE
OTHER INFORMATION: human IL-12p40 variant E81A/F82A
Query Match 100.0%; Score 1641; Length 328;
Best Local Similarity 100.0%;
Matches 306; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKAA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKAA 82
Qy 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 142
Qy 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 202
Qy 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 262
Qy 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 263 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 322
Qy 301 ASVPCS 306
||||||
Db 323 ASVPCS 328
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the IL-12 / PD-L2 immunomodulatory molecule as taught by Krupnick et al. with the IL-12 variants of Garcia et al. because Krupnick et al. also teaches an IL-2 / PD-L2 immunomodulatory molecule having IL-2 variants with modified affinity for IL-2 receptors to beneficially reduce toxicities associated with IL-2 cancer treatments (see, e.g., Krupnick et al. at para. [0236], [0256], claim 102); and Garcia et al. teaches the claim-recited IL-12 variants having modified affinity for IL-12 receptors and having the same beneficial effect of lower toxicity in the context of IL-12 cancer treatments (see, e.g., Garcia et al. at para. [0102]). The person of ordinary skill in the art would be motivated to include the variants of Garcia et al. to reduce toxicity when administering the IL-12 / PD-L2 immunomodulatory molecule as taught by Krupnick et al. because there is a reasonable expectation of success in reducing the toxicity of an IL fusion protein by including IL variants known to reduce toxicity of the IL protein itself. Although the motivation to combine Krupnick et al. and Garcia et al. was not gleaned from the instant specification, it is notable that Applicant has included the IL-12 variants for the same reason—to reduce the toxicity of the claim recited IL-12 fusion proteins. See e.g., Example 10 of the instant specification.
Furthermore, it is obvious to combine prior art elements according to known methods to yield predictable results. In this case, each element (e.g., the IL-12 / PD-L2 immunomodulatory molecule of Krupnick et al. and the beneficial IL-12 variants of Garcia et al.) merely performs the same function as it does separately. A person of ordinary skill in the art would also have a reasonable expectation of success in reducing harmful side effects caused by the IL-12 in the fusion protein by including the variants. It was therefore predictable that the IL-12 variants in the IL-12 / PD-L2 immunomodulatory molecule would result in an improved IL-12 / PD-L2 immunomodulatory molecule with better tolerability characteristics for administration to a subject in need thereof.
Conclusion
13. No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights