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
2. The amendment filed 06/17/2026 is acknowledged and has been entered.
Claims 1, 3 and 8 are amended. Claim 2 has been canceled. New claim 19 has been added.
Claims 1 and 3-19 are pending in the application. Claims 13-18 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025.
4. Claims 1, 3-12 and 19 have been examined.
Grounds of Objection and Rejection Withdrawn
5. Unless specifically reiterated below, Applicant’s amendment and/or arguments have obviated or rendered moot the grounds of objection and rejection set forth in the previous Office action mailed 03/18/2026.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
6. 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 of this title, 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.
7. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
8. Claims 1, 3-10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Debinski et al. (US 20090123371, published on May 14, 2009, IDS).
Claims 1, 3-10 and 12 are herein drawn to a construct comprising, in combination: a ligand that binds to EphA2, EphA3, and EphB2; and at least one effector molecule, wherein said construct is a fusion protein and/or a covalent conjugate.
Debinski et al. teach ligands of the Eph receptors (e.g. EphA2, EphA3, and EphB2) include ephrins (e.g. ephrinA1 or ephrinA5 also known as eA5); see entire document, e.g. [0054-0057], [0089]. Debinski et al. teach ephrinA1 in monomeric form is conjugated to a therapeutic agent; see claim 12, [0014-0017].
Debinski et al. teach glycosylation (instant claim 4); see [0069].
Debinski et al. teach wherein said therapeutic agent comprises a Pseudomonas exotoxin or a chemotherapeutic agent (instant claims 5, 10 and 12); see claim 14.
Debinski et al. teach dimeric ephrinA1-Fc; see [0045]. Fc of Debinski et al. meets the limitations of the instant claimed a cytosol localization element and a subcellular compartment (instant claims 6-7).
Debinski et al. teach ephrinA1 fused to Fc via a polypeptide linker (instant claims 8-9); see [0090].
Although Debinski et al. teach ephrinA5; however, Debinski et al. do not teach ephrinA5 is conjugated to a therapeutic agent.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the reference so as to have ephrinA5 conjugated therapeutic agent. One would have been motivated to do so because simple substitution of one ephrin (e.g. ephrinA1) for another ephrin (e.g. ephrinA5) of Debinski et al. would obtain predictable results.
Given the examination guidelines for determining obviousness under 35 U.S.C. 103 in view of the Supreme Court decision in KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007) and the Examination Guidelines set forth in the Federal Register (Vol. 72, No. 195, October 10, 2007) and incorporated recently into the MPEP (Revision 9, March 2014), the following rationales to support rejection under 35 U.S.C. 103(a) are noted:
A) Combining prior art elements according known methods to yield predictable results.
B) Simple substitution of one known element for another to obtain predictable results.
C) Use of known technique to improve similar devices (methods, or products) in the same way.
D) Applying known technique to a known device (method, or product) ready for improvement to yield predictable results.
E) “Obvious to try” --- choosing form a finite number of identified, predictable solutions, with a reasonable expectation of success.
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art.
G) Some teachings, suggestion, or motivation in the prior art that would lead to one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In this case, simple substitution of one ephrin (e.g. ephrinA1) for another ephrin (e.g. ephrinA5) of Debinski et al. would obtain predictable results.
Obviousness is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
9. Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Debinski et al. (US 20090123371, published on May 14, 2009, IDS) as applied to claims 1, 3-10 and 12 above, and further in view of Carvalho et al. (Nature Neuroscience, 2006, 9(3): 322-330, IDS).
Claims 3-4 are herein drawn to the construct of claim 1, wherein said ligand is a mutant of eA5.
The teachings of Debinski et al. have been set forth in the above rejection of claims 1, 3-10 and 12 under 35 U.S.C. 103.
Although Debinski et al. teach ligands of the Eph receptors (e.g. EphA2, EphA3, and EphB2) include ephrinA5 (also known as eA5), Debinski et al. do not teach a mutant of ephrinA5.
However, this deficiency is remedied by Carvalho et al.
Carvalho et al. teach a method of introduction of point mutations in ephrinA5 at positions 126 and 129; see entire document, e.g. sixth paragraph of left col. on page 328.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references so as to make a mutant of ephrinA5 as a ligand of EphA2, EphA3 and EphB2. One would have been motivated to do so because Debinski et al. teach ephrinA5 as a ligand of EphA2, EphA3 and EphB2; Carvalho et al. teach a method of introduction of point mutations in ephrinA5. Thus, one of ordinary skill in the art would have a reasonable expectation of success that by combining the teachings of the references so as to make a mutant of ephrinA5 as a ligand of EphA2, EphA3 and EphB2 to arrive claimed invention of having point mutations in ephrinA5, because a method of introduction of point mutations in ephrinA5 as taught by Carvalho et al.
10. Claims 1 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Debinski et al. (US 20090123371, published on May 14, 2009, IDS) as applied to claims 1, 3-10 and 12 above, and further in view of Maithal et al. (WO 2007057922, 24 May 2007).
Claim 11 is herein drawn to the construct of claim 10, wherein E is (KLAKLAK)2(SEQ ID NO:1).
Claim 12 is herein drawn to the construct of claim 8, wherein D is a nuclear localization element.
The teachings of Debinski et al. have been set forth in the above rejection of claims 1, 3-10 and 12 under 35 U.S.C. 103.
Debinski et al. do not teach E is (KLAKLAK)2(SEQ ID NO:1), and D is a nuclear localization element.
However, this deficiency is remedied by Maithal et al.
Maithal et al. teach that peptide “KLAKLAKKLAKLAK" is selectively toxic to angiogenic endothelial cells and showed anti-cancer activity; see entire document, e.g., page 4 lines 13-15.
The peptide “KLAKLAKKLAKLAK" of Maithal et al., should be produced in nuclear; thus, the peptide is a nuclear localization element.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references so as to have a construct comprises ephrinA5-linker-Fc-KLAKLAKKLAKLAK. One would have been motivated to do so because Debinski et al. teach ephrinA5-linker-Fc- chemotherapeutic agent; Maithal et al. teach that peptide “KLAKLAKKLAKLAK" is selectively toxic to angiogenic endothelial cells and showed anti-cancer activity. Thus, one of ordinary skill in the art would have a reasonable expectation of success that by combining the teachings of the references so as to substitute the therapeutic agent of Debinski et al. for another therapeutic agent (KLAKLAKKLAKLAK) of Maithal et al., because simple substitution of the therapeutic agent of Debinski et al. for another therapeutic agent (KLAKLAKKLAKLAK) of Maithal et al. would obtain predictable results.
Given the examination guidelines for determining obviousness under 35 U.S.C. 103 in view of the Supreme Court decision in KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007) and the Examination Guidelines set forth in the Federal Register (Vol. 72, No. 195, October 10, 2007) and incorporated recently into the MPEP (Revision 9, March 2014), the following rationales to support rejection under 35 U.S.C. 103(a) are noted:
A) Combining prior art elements according known methods to yield predictable results.
B) Simple substitution of one known element for another to obtain predictable results.
C) Use of known technique to improve similar devices (methods, or products) in the same way.
D) Applying known technique to a known device (method, or product) ready for improvement to yield predictable results.
E) “Obvious to try” --- choosing form a finite number of identified, predictable solutions, with a reasonable expectation of success.
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art.
G) Some teachings, suggestion, or motivation in the prior art that would lead to one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In this case, simple substitution of the therapeutic agent of Debinski et al. for another therapeutic agent (KLAKLAKKLAKLAK) of Maithal et al. would obtain predictable results.
Obviousness is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Conclusion
11. Claims 1 and 3-12 are rejected. Claim 19 is objected to as being dependent upon a rejected base claim.
12. Applicant's amendment necessitated the new ground(s) of objection/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.
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/YAN XIAO/Primary Examiner, Art Unit 1642
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