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
The amendment filed May 18, 2026, is acknowledged and has been entered. Claims 198, 200, 209, 211, 218, 229 and 231 have been amended. Claims 203, 214, 221, 223 and 234 have been canceled.
Claims 198, 200-202, 206-213, 215-222, 226-233 and 235-237 are pending.
Claims 207, 215-217, 227 and 235-237 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention or non-elected species of invention, there being no allowable generic or linking claim.
Claims 198, 200-202, 206, 208-213, 218-222, 226 and 228-233 are under examination. Group 1 and the species of a complex with one binding moiety and one signaling domain, a modified human interferon alpha 2 (IFNa2) signaling agent having at least 95% identity with SEQ ID NO: 1 and a R149A mutation, IgG Fc chains of the Fc domain and that one or more mutations to the Fc domain results in knob-in-hole pairing along, signaling agent IL-2 or IL-15 and targeting moieties of VHH, a Fab, a Fab' and a F(ab')2 are under consideration.
Information Disclosure Statement
The information disclosure statement has been considered.
Grounds of Rejection Withdrawn
Applicant's amendment has obviated or rendered moot the grounds rejection set forth in the previous Office action.
New Claim Rejections
Claim Rejections - 35 USC § 112
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 208 and 228 are indefinite in the recitation of “wherein the one or more mutations to the Fc domain results in a knob-in-hole pairing of the Fc domain.” Notably, claims 198 and 218 recite a chimeric protein with mutations in an Fc that reduce effector functions, so this phrase lacks antecedent basis and it cannot be determined which (if any) one of more mutations are being referred to.
Thus, the claims fail to delineate the subject matter that Applicant regards as the invention with the requisite degree of clarity and particularity to permit the skilled artisan to know or determine infringing and non-infringing subject matter and thereby satisfy the requirement set forth under 35 U.S.C. § 112, second paragraph.
Canceling claims 208 and 228 would obviate this rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 198, 200-202, 206, 208-213, 218-222, 226 and 228-233 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2017/165464 A1, IDS), Lazar et al (WO 2016/164480 A1) and Kley et al (WO 2017/077382 A1, IDS).
Loew et al discloses a heterodimeric chimeric complex comprising a targeting moiety that binds to a target and only one signaling agent, wherein the only one signaling agent is a modified signaling agent (such as an interleukin (IL-2 or IL-15) or interferon) that has reduced affinity for or activity at the signaling agent's receptor relative to the unmodified signaling agent; and an IgG1 Fc domain, the Fc domain comprising two Fc chains and having one or more mutations promoting Fc chain pairing of the Fc domain (knob-in hole mutations) and having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, and/or stabilizes a hinge region in the Fc domain, wherein the Fc domain is heterodimeric as relating to the targeting moiety and the modified signaling agent, relative to each other, such that they are in trans orientation and wherein the targeting moiety restores the modified signaling agent's affinity for or activity at the signaling agent's receptor and further comprising a linker (see entire document, e.g., pages 4, 18, 28, 41, 42, 72, 77, 84, 110-111, and 113-114 and 116, Figure 5A and claims).
Loew et al discloses the Fc region can be from IgG (see page 71).
Loew et al discloses chimeric protein can comprise a targeting moiety or second targeting moiety that binds the CD20 tumor antigen and (see page 103).
Loew et al discloses the chimeric proteins can recruit immune cells to the tumor microenvironment (see pages 59-61 and 95).
Loew et al discloses the targeting domain can be a VHH or a Fab (see pages 5, 72 and 80).
With respect to claims 211 and 231, the targeting moiety upon binding either neutralizes or does not neutralize so the molecule of the prior art would have one of these functions. Furthermore, with respect to the claimed functions in the claims, it is noted that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. Therefore, as the prior art teaches products of identical structure to those claimed, the products of the prior art have these functions.
Furthermore, the Office does not have the facilities for examining and comparing Applicant's products with the products of the prior art in order to establish that the products of the prior art possesses the same material, structural, and functional characteristics as Applicant’s products. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the products to which the claims are directed are different than that taught by the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA, 1977) and Ex parte Gray, 10 USPQ2d 1922 1923 (PTO Board of Patent Appeals and Interferences, 1988 and 1989).
Loew et al does not disclose an IgG1 Fc domain with comprising mutations L234A, L235A and P329G that reduce effector functions of the Fc domain or a signaling agent that is a modified human interferon alpha 2 (IFNa2) signaling agent that has reduced affinity activity at IFNAR relative to unmodified human IFNa2, the modified human IFNa2 signaling agent having at least 95% identity with SEQ ID NO:1 or 2 with a R149A mutation.
Lazar et al disclose Fc variants of human IgG1 comprising alterations at positions L234A, L235A and P329G that reduces effector function (see ¶ 174).
Kley et al discloses chimeric protein comprising a targeting moiety a Fc fusion and a human IFNa2, having at least 95% identity with SEQ ID NO:1 or 2 with a R149A mutation (see pages 12-13, 37 and 53).
Kley et al discloses the mutation allows for the modified soluble agent to have reduced systemic toxicity, reduced side effects, and reduced off-target effects relative to unmutated, e.g. the wild type form of the soluble agent (see page 5).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to alter positions L234A, L235A and P329G in IgG1 to that reduce effector function and substitute human interferon IFNa2, having at least 95% identity with SEQ ID NO:1 or 2 with a R149A mutation for the interferon signaling agent of Loew et al in their constructs because such an Fc domain would have the advantage of reduced effector function that is not desired in Fc chimeric proteins whose purpose is target a interferon signaling agent and because a mutated human interferon IFNa2 with lower affinity would have the advantage of reduced systemic toxicity, reduced side effects, and reduced off-target effects relative to unmutated, e.g. the wild type form of the soluble agent.
In this case, making such constructs would be considered combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Finally, one of skill in the art would have had a reasonable expectation of success in making such constructs because the prior art evidences that genetic engineering techniques to make such mutations and fuse such domains into recombinant protein complexes were known in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Claims 198, 200-202, 206, 208-213, 218-222, 226 and 228-233 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2017/165464 A1, IDS), Lazar et al (WO 2016/164480 A1) and Tavernier et al (WO 2013/107791 A1, IDS).
Loew et al discloses a heterodimeric chimeric complex comprising a targeting moiety that binds to a target and only one signaling agent, wherein the only one signaling agent is a modified signaling agent (such as an interleukin (IL-2 or IL-15) or interferon) that has reduced affinity for or activity at the signaling agent's receptor relative to the unmodified signaling agent; and an IgG1 Fc domain, the Fc domain comprising two Fc chains and having one or more mutations promoting Fc chain pairing of the Fc domain (knob-in hole mutations) and having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, and/or stabilizes a hinge region in the Fc domain, wherein the Fc domain is heterodimeric as relating to the targeting moiety and the modified signaling agent, relative to each other, such that they are in trans orientation and wherein the targeting moiety restores the modified signaling agent's affinity for or activity at the signaling agent's receptor and further comprising a linker (see entire document, e.g., pages 4, 18, 28, 41, 42, 72, 77, 84, 110-111, and 113-114 and 116, Figure 5A and claims).
Loew et al discloses the Fc region can be from IgG (see page 71).
Loew et al discloses chimeric protein can comprise a targeting moiety or second targeting moiety that binds the CD20 tumor antigen and (see page 103).
Loew et al discloses the chimeric proteins can recruit immune cells to the tumor microenvironment (see pages 59-61 and 95).
Loew et al discloses the targeting domain can be a VHH or a Fab (see pages 5, 72 and 80).
With respect to claims 211 and 231, the targeting moiety upon binding either neutralizes or does not neutralize so the molecule of the prior art would have one of these functions. Furthermore, with respect to the claimed functions in the claims, it is noted that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. Therefore, as the prior art teaches products of identical structure to those claimed, the products of the prior art have these functions.
Furthermore, the Office does not have the facilities for examining and comparing Applicant's products with the products of the prior art in order to establish that the products of the prior art possesses the same material, structural, and functional characteristics as Applicant’s products. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the products to which the claims are directed are different than that taught by the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA, 1977) and Ex parte Gray, 10 USPQ2d 1922 1923 (PTO Board of Patent Appeals and Interferences, 1988 and 1989).
Loew et al does not disclose an IgG1 Fc domain with comprising mutations L234A, L235A and P329G that reduce effector functions of the Fc domain or a signaling agent that is a modified human interferon alpha 2 (IFNa2) signaling agent that has reduced affinity activity at IFNAR relative to unmodified human IFNa2, the modified human IFNa2 signaling agent having at least 95% identity with SEQ ID NO:1 or 2 with a R149A mutation.
Lazar et al disclose Fc variants of human IgG1 comprising alterations at positions L234A, L235A and P329G that reduces effector function (see ¶ 174).
Tavernier et al discloses a composition comprising a targeting construct, wherein the targeting construct comprises: a mutated human interferon alpha 2, the mutated human interferon alpha 2 having R149A mutation and a reduced affinity for IFNAR2 as compared to the wild-type human interferon alpha 2; and a targeting moiety, the targeting moiety comprising an antibody, wherein the targeting moiety restores the reduced affinity of the mutated human interferon alpha 2 for IFNAR2 on targeted cells (see entire document, e.g., abstract, description, figures, examples and page 9).
Tavernier et al discloses the mutation allows for the modified soluble agent to have reduced systemic toxicity, reduced side effects, and reduced off-target effects relative to unmutated, e.g. the wild type form of the soluble agent (see page 2).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to substitute human interferon IFNa2, having at least 95% identity with SEQ ID NO:1 or 2 with a R149A mutation for the interferon signaling agent of Loew et in their constructs because such an Fc domain would have the advantage of reduced effector function that is not desired in Fc chimeric proteins whose purpose is target a interferon signaling agent and because a mutated human interferon IFNa2 with lower affinity would have the advantage of reduced systemic toxicity, reduced side effects, and reduced off-target effects relative to unmutated, e.g. the wild type form of the soluble agent.
In this case, making such constructs would be considered combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Finally, one of skill in the art would have had a reasonable expectation of success in making such constructs because the prior art evidences that genetic engineering techniques to make such mutations and fuse such domains into recombinant protein complexes were known in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Conclusion
No claims are allowed. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US 9,878,014 B2 (Tavernier et al, IDS) disclose a composition comprising a targeting construct, wherein the targeting construct comprises: a mutated human interferon alpha 2, the mutated human interferon alpha 2 having R149A mutation and a reduced affinity for IFNAR2 as compared to the wild-type human interferon alpha 2; and a targeting moiety, the targeting moiety comprising an antibody directed to Her2, wherein the targeting moiety restores the reduced affinity of the mutated human interferon alpha 2 for IFNAR2 on targeted cells.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is 571-272-9935. The examiner can normally be reached Mon-Fri
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu, can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
August 21, 2026
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