Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claim Status
Applicant’s amendment filed August 5, 2025 has been received and entered.
Claim 20 has been amended.
Claims 1-19, 21-22, and 25-26 were previously canceled.
Claims 20, 23-24, and 27 are pending and under consideration.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of Application No. 16/020,447 filed on June 27, 2018, which is a continuation of Application No. 15/717,205 filed on September 27, 2017, which is a continuation of Application No. 15/278,854 filed on September 28, 2016, which is a continuation of Application No. 14/372,730 filed on July 16, 2014, which is a 371 of PCT/EP2013/050787 filed January 7, 2013, which claims the benefit of EP Application No. 12305075.9 filed on January 20, 2012.
Claim Rejections - 35 USC § 112 - Maintained
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.
Claims 20, 23-24, and 27 stand rejected under 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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. Specifically, there is insufficient written description to demonstrate the Applicant was in possession of the claimed genus of camelid heavy chain antibodies (VHH) that bind leptin receptor.
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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. See MPEP § 2163.
The instant claims have been amended to recite a cytokine-antibody fusion construct comprised of a mutated human INFa2 with a reduced affinity for IFNAR2, and a variable domain of a camelid heavy chain antibody (VHH) that binds leptin receptor and restores reduced affinity of INFa2 for IFNAR2 on target cells that express leptin receptor.
The state of the art at the time of filing recognized that the hormone leptin was involved in the pathology of several diseases including autoimmune diseases, atherosclerosis, and cancer. At the time of filing both high-affinity leptin muteins that act as receptor antagonists which have extended persistence in the circulation in vivo, and humanized mAbs that block leptin receptor activity were being investigated [Gertler, 2006; see pg. 377, Conclusion]. However, the use of recombinant nanobodies that target the leptin receptor and block the ligand-induced conformational switch without interfering with the leptin–leptin receptor interaction were just being contemplated. As such, the use of leptin VHH antibodies were identified as having high therapeutic potential, as nanobodies provide several advantages over traditional antibodies due to their small size, short half-life, and ease of modification [Gertler, 2006; see pg. 377, col. 1].
The instant specification discloses two nanobodies (4-11 and 4-10) directed against the murine leptin receptor [0040, 0041] which were used to make three IFNa2 fusion protein constructs that confer reduced affinity to IFNAR2 [0047]. It is well understood in the art that protein folding and formulation are complex and fairly unpredictable processes, thus one cannot readily extrapolate the properties of the leptin receptor VHH antibody recited in the instant invention to other possible leptin receptor VHH antibodies, as the properties of the leptin receptor VHH antibody are not predictive of the full genus of proteins that can be generated.
Applicant has argued, starting on page 3 of the reply received August 5, 2025, that they have established the necessary structure-function correlation between the two VHH nanobodies recited in the instant specification and the full genus of VHH that bind leptin receptor, because the amended claims recite the VHH specifically targets leptin receptor expressed on target cells, allowing binding of mutated IFNa2 to IFNAR and restoration of IFNa2 activity.
Applicant’s arguments were considered but they were not deemed persuasive.
Specifically, the instant specification does not disclose the amino acid sequences for the VHH that bind leptin receptor, including the three CDR regions which are critical for antigen binding specificity. Thus, the instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics.
De Genst et al. (2005) teach that since the three antigen binding loops provided by a VL are absent in the antigen-binding site in the VHH, the three CDRs of the VHH are critical for antigen binding specificity and affinity and that cloning VHH antibody (e.g. by phage display or camelizing using a synthetic library) can be disadvantageous since lower affinity binders are often obtained that need additional mutagenesis steps [see pg. 188, col. 2 and pg. 196, col. 1). Further, Tereshko et al. (2008), in engineering VHH that binds RNase from a yeast expression library, teach that only a small fraction of the library was both expression and antigen-binding, indicating that some of the mutations or combinations thereof are detrimental to the VHH antigen binding and stability [pg. 1176-1178]. Additionally, Sircar et al. (2011) teach that the CDRs of the VHH antibody adopt diverse conformations not classifiable by established canonical rules and thus, VHH structures with biological relevant conformations of the unique CDR loops are required to understand VHH-antigen interaction [pg. 6357-6358].
Moreover, while it is not required that all potential embodiments be disclosed, the written description doctrine requires that sufficient representing species be disclosed in order to support the entire genus. Rather than simply listing various embodiments, the usual approach is to also describe common structural features of the species. See Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997) and Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
The disclosure of two species of VHH (4-11 and 4-10) directed against the murine leptin receptor is not sufficient support an entire genus VHH as recited. The common structural elements essential to binding leptin on cells that express leptin receptor requires a full length VHH with minimally defined amino acid sequences of three CDRs. “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co., 43 USPQ2d 1398 (Fed. Cir. 1997). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406. Thus, in the absence of disclosure of relevant, identifying characteristics of the “VHH that binds leptin receptor” (namely the amino acid sequences of CDR1, CDR2, and CDR3), there is insufficient written disclosure under 35 U.S.C. 112, first paragraph for the claimed methods that depend upon the camelid VHH that binds leptin receptor.
Claims 23-24, and 27 are included in the rejection because they depend from or otherwise require all the limitations of rejected independent claim 20.
Claim Rejections - 35 USC § 103 - Maintained
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 20, 23-24, and 27 stand rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Silver et al. (US 2011/0274658 A1) (“Silver”) in view of Tavernier et al. (WO 2006/053883 A1; cited in IDS dated 9 February 2021) (“Tavernier”).
The instant claims are drawn to a composition comprising a targeting construct comprising a mutated human interferon alpha 2 having a mutation selected from R149A, L153A, and M148A and a reduced affinity for IFNAR2 as compared to the wild-type; and a targeting moiety comprising a variable domain of a camelid heavy chain antibody (VHH) that binds leptin receptor, that restores the reduced affinity of the mutated human interferon alpha 2 for IFNAR2 on targeted cells that express leptin receptor, wherein the targeting construct is a recombinant fusion protein with a linker that connects the mutated interferon alpha 2 and the variable chain of the VHH; and a pharmaceutical composition comprising the targeting construct and a suitable excipient.
The specific places where Silver and Tavernier teach the particular limitations are set forth in the Office Action mailed May 6, 2025.
Applicant has argued, on page 4 of the reply received August 5, 2025, that there is no motivation provided in either Silver or Tavernier, whether taken alone or in combination, that would guide one of ordinary skill in the art to arrive at the particular claimed construct of claim 20 - a recombinant fusion protein targeting construct comprising a mutated human interferon alpha 2, the mutated human interferon alpha 2 having a mutation selected from R149A, L153A, and M148A that confers a reduced affinity for or activity at IFNAR2 as compared to the wild-type human interferon alpha 2, and a targeting moiety comprising a VHH that binds leptin receptor, where the targeting moiety restores the reduced affinity of the mutated human interferon alpha 2 for IFNAR2 on targeted cells that express leptin receptor. Applicant further argues the use of the presently recited targeting moiety comprising a VHH that binds leptin receptor is meant to target the attenuated human interferon alpha 2 rather than signal at the leptin receptor.
Applicant’s arguments were fully considered but are not deemed persuasive.
Specifically, Silver discloses a targeting construct comprising a variant activity element that comprises a mutation that reduces its binding affinity for its receptor on a target cell by 10-100%, and a second element that binds to a second receptor on the same target cell. The first and second elements may be connected by a linker that allows both elements to bind simultaneously to the first and second receptors on the target cell [0010]. Such constructs can be used to treat cancer, or to selectively target any activity mediated by a cell surface receptor to target cells that selectively express a cell surface marker. Thus, the chimeric construct can be used to target cytotoxic or cytostatic activity to any cells associated with a disease or disorder, such as cancer cells, immune cells associated with allergic or chronic inflammatory disorders or reactions, infected cells, pathogen cells, cells that are degenerating, or any other target cells of interest [0019].
Silver further discloses the targeting element has sufficient affinity to target the chimeric protein on the target cell surface [0045] and includes single domain antibodies which bind the target receptor [0049]. The activity element is a mutated variant with reduced binding compared to the wild-type protein, and wherein binding of the chimeric protein to a cell is driven by the binding of the targeting element to its receptor. Therefore, the chimeric protein cannot significantly bind to cells that have only the activity element receptor and not the targeting element receptor, because the inherent binding of the activity element is simply too weak. The presence of one or more mutations in the activity element can be essential to reduce side effects from activation of non-target cells [0057].
IFNa is used in the treatment of hepatitis B, hepatitis C, and certain forms of cancer. Side effects of IFNa treatment include flu-like symptoms, depression, and myelosuppression, which limit the dose and limit the therapeutic index [0121].
Silver constructed chimeric proteins consisting of wild-type and mutant forms of IFNa2 as the activating element, wherein an IFNa R149A mutant protein reduced binding to IFNAR2 by 200x. However, chimeric activators with IFNa mutations fused to a targeting element [EGF] restored IFNa signaling to levels higher than the corresponding IFNa mutants alone [0129], while activation was undetectable in cells with only IFNAR [0131].
In addition, Silver teaches 88 examples of targeting elements, including leptin [0054], demonstrating the versatility of the construct, not just a part of a “laundry list” of target proteins as Applicant asserts. Silver also teaches TNFa as an activity element to demonstrate the breadth of the chimeric activator concept, wherein each element (activity element, a linker, and a targeting element) of the construct can be replaced with an alternative component that is structurally different and/or has a different biological function [0145].
In addition, Tavernier teaches the same camelized VHH that binds the murine leptin receptor as recited in the instant specification (nanobody 4-11) [0041].
Given that Silver teaches a chimeric protein that comprises a mutated IFNa2 as the activating element with EGF as the targeting agent to target cells having EFGR, artisans would have a reasonable expectation of success in utilizing other cell surface targets, such as the leptin receptor, especially as Silver teaches over 80 proteins suitable as targeting moieties. A person having ordinary skill in the art would be motivated to modify the chimeric variant IFNa construct taught by Silver to include leptin receptor as the target element because leptin is associated with many conditions including cancer, providing an attractive target. For example, Silver teaches that IFNa is effective against breast cancer, but too toxic for clinical use. Therefore, by using a less active variant of IFNa (e.g. R149A) in a chimeric targeting construct comprising a targeting element with high affinity to another receptor on the surface of breast cancer cells, the toxicity of IFNa can be avoided while retaining desired cytotoxic activity. Because leptin receptor is expressed on cancer cells, including breast cancer cells (Garofalo, 2006), one would have more than a reasonable expectation of success in targeting the variant IFNa construct using a VHH that binds to leptin receptor with high affinity as taught by Tavernier, especially as Silver teaches separate constructs comprising IFNa R149A as an activity element and leptin as a targeting element and that each element (activity element, a linker, and a targeting element) of the construct can be replaced with an alternative component. As stated above, one would be motivated to use a VHH in the construct because nanobodies provide several advantages over traditional antibodies due to their small size, short half-life, and ease of modification [Gertler, 2006; see pg. 377, col. 1]. Thus, the combination of prior art references as combined provided a prima facie case of obviousness and the rejection is maintained.
Double Patenting – Withdrawn
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 20, 23-24, and 27 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, and 14 of U.S. Patent No. 10,906,985 B2, in view of Tavernier et al. (WO 2006/053883 A1) (“Tavernier”), and in further view of Silver et al. (US 2011/0274658 A1) (“Silver”).
In view of Applicant’s arguments in the reply received August 5, 2025 [pg. 5], the previous nonstatutory double patenting rejection is withdrawn. Specifically, Applicant has shown that the ‘985 patent is drawn to consensus interferon, not mutated human interferon alpha 2 as recited in the instant claims.
Claims 20, 23-24, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 9,732,135 B2, in view of Tavernier et al. (WO 2006/053883 A1) (“Tavernier”).
In view of the Applicant’s arguments in the reply received August 5, 2025 [pg. 6], the previous nonstatutory double patenting rejection is withdrawn. Specifically, the ‘135 patent is drawn to human IFNa2 comprising an R120E mutation which provides antagonism to a targeting moiety directed to CD20, which is not the same scope as the instant claims.
Terminal disclaimers have been filed over the following US Patents rendering the previous grounds of nonstatutory double patenting rejections moot.
US Patent No. 10,946,070
US Patent No. 10,034,919
US Patent No. 9,492,562
US Patent No. 9,878,014
Conclusion
No claims are allowed.
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 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.
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/MAUREEN VARINA DRISCOLL/
Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644