DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a U.S. national phase of International Application No. PCT/IB2021/057170, filed on 08/04/2021, which claims domestic benefit to US provision application 63/061,759, filed 08/05/2020.
Claim Status
The Amendment, filed on 08/22/2023, is acknowledged in which:
Claims 5, 15-18, 28-29, 33-37, 39-42, 44-47, 49, 52-55, 57-59, 61-69, 74, 78-79, 81-83, 85-90, 94-110, 112-115, 117-122, and 125-135 are canceled.
Claims 3, 6-14, 19-25, 27, 30-32, 38, 43, 48, 50-51, 56, 60, 70-72, 75, 77, 80, 84, 91-93, 111, 116, and 123-124 are currently amended.
Claims 1-2, 4, 26, 73, and 76 are original.
Claims 1-4, 6-14, 19-27, 30-32, 38, 43, 48, 50-51, 56, 60, 70-73, 75-77, 80, 84, 91-93, 111, 116, and 123-124 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 08/15/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. SPECHT et al (2018) abstracts CT131 and P2-09-13 (citation numbers 261 and 262) have been placed in the application file, but the information referred to therein has not been considered. All other references, where not lined through, have been considered.
Specification
The use of the term “KinExA” (¶ [0173]); “CellTrace” (¶ [0189]); “Alexa Fluor”, “Oregon Green”, “Bodipy”, and “Texas red” (¶ [0215]); “THIOMAB” (¶ [0227]); “Percoll” and “Ficoll” (¶[0317]); “Dynabeads” (¶ [0332] and [0372]); “MACS” (¶ [0332]); “CliniMACS” (¶ [0341] and [0342]); “CliniMACS Prodigy” (¶ [0343]); “BIAcore” (¶ [0452]); “Megalign” (¶[0489]); “GlutaMAX” (¶ [0523]); which are trade names or marks used in commerce, has been noted in this application. Each 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.
Claim Objections
Applicant is advised that should claim 72 be found allowable, claim 73 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 26 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The instant claim recites the antibody of claim 25 (an antigen binding fragment of claim 1) as a single domain antibody (3 CDRs) were the base claim (claim 1) recites an antibody or antigen binding fragment comprising a VH and VL comprising 6 CDRs. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-4, 6-9, 14, 19-22, 25-27, 30-32, 38, 43, 48, 50-51, 56, 60, 70-73, 75-77, 80, 84, 91-93, 111, 116, and 123-124 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 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.
Claim 1 is drawn to an anti-idiotype antibody or antigen binding fragment thereof that binds to an anti-ROR1 target antibody or antigen binding fragment thereof, comprising VH and VL domains, wherein the VH/VL comprise CDRs set forth in recited VH/VL pairs: (a) SEQ ID NOs: 24 and 25; (b) SEQ ID NOs: 24 and 26; (c) SEQ ID NOs: 47 and 48; or (d) SEQ ID NOs: 65 and 66.
Claim 2 is drawn to an anti-idiotype antibody or antigen binding fragment thereof that binds to an anti-ROR1 target antibody or antigen binding fragment thereof, comprising VH and VL domains, wherein the VH/VL comprise 6 CDRs set forth in (a) SEQ ID NOs: 29, 30, 31, 36, 38, and 40; (b) SEQ ID NOs: 29, 30, 31, 37, 39, and 40; (c) SEQ ID NOs: 51, 52, 53, 58, 59, and 60; or (d) 69, 70, 71, 76, 77, and 78
Claim 4 is drawn to an anti-idiotype antibody or antigen binding fragment thereof that binds to an anti-ROR1 target antibody or antigen binding fragment thereof, comprising VH and VL domains, wherein the VH/VL comprise at least 90% sequence identity to the VH/VL pairs set forth in: (a) SEQ ID NOs: 24 and 25; (b) SEQ ID NOs: 24 and 26; (c) SEQ ID NOs: 47 and 48; or (d) SEQ ID NOs: 65 and 66.
Claim 26 is drawn to the anti-idiotype antibody or antigen binding fragment thereof of claim 25 (dependent on claim 1; i.e. species with 6 CDRs), wherein the antigen binding fragment is selected from various species including a single domain antibody.
The instant specification discloses sufficient three species of antibodies with evidence of anti-idiotype properties against anti-ROR1 CAR containing an ECD composted of an anti-ROR1 scFv (SEQ ID NO:2): F101, F107, and F112. Examiner notes claimed species that correspond to F107 and F112 (i.e. (c) and (d) species recited within the instant claims) comply with written description requirements. Clone F101, however, is disclosed to have two light chain species, a “more prevalent VL” and “less prevalent VL” (Table E3), that were observed at a 4:1 expression ratio (SEQ ID NO: 25 comprising LCDRs 1 and 2 encoded within SEQ ID NOs: 36 and 38, respectively; and SEQ ID NO: 26 comprising LCDRs 1 and 2 encoded within SEQ ID NOs: 37 and 39, respectively), from (a) and (b) species recited in claim 1 (¶ [0516]). However, it is unclear based on the binding assays which claimed VL species is responsible for the specificity of clone F101. Furthermore, the specification does not provide guidance for arriving at antibodies with up to 10% variance within sequences comprising critical binding paratopes (i.e. instant claim 4) nor single domain antibodies (comprising only 3 CDRs) that would predictably retain anti-ROR1 target antibody binding.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guide lines for claims drawn to antibodies, which can be found at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen.
Prior art dictates that antibody specificity depends on antibody structure, particularly in the paratope formed from a complement of six CDRs. It is generally understood that residues differences in the CDRs can have unpredictable effects to epitope binding and that each construct requires function testing.
Rabia (Biochem Eng J. 2018 Sep 15;137:365-374.) teaches that antibody-antigen binding specificity is primarily mediated by the six CDRs within the sequences of variable heavy and variable light chains (Introduction, paragraph 1). Given the chemical diversity possible within combined CDRs alone (~20 different amino acids at ~60 sites), not all combinations can result in viable antibodies suitable for therapeutic applications. An outstanding challenge in the field is that optimizing antibodies based on antigen affinity can lead to defects in other properties such as stability, specificity, and solubility (page 366, column 1, ¶ 2). Even natural antibody maturation, which relies on random somatic mutations, is followed by clonal selection for antibodies with improved affinity and/or with mutations that compensate for destabilizing affinity enhancing mutations (page 366, column 2, paragraph 2). It is expected that most somatic mutations that increase affinity, such as those that increase hydrophobicity or charge, can also reduce specificity. Based on these teachings, introducing variation in antibody structure, particularly in the arrangement of CDR regions, requires thorough testing to ensure suitable binding specificity and antibody stability.
Herold (Sci Rep. 2017;7(1):12276) teaches antigen binding is "affected by each CDR loop differently" and changes thereto "can in principle affect antigen binding affinity in an unpredictable way" (pg. 14, ¶ 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex (pg. 14, ¶ 3).
Bradbury (MAbs. 2018;10(4):539-546) teaches that cross-reactive recognition of epitopes can arrive from co-expression of additional productive, but non-target-binding, antibody chains, which arise from the way hybridomas are generated (Introduction). Of the hybridomas evaluated, 28.6% contained additional productive VL domains (Table 1). The expression of additional chains degraded properties of the antibodies, including specificity, binding signal and/or signal-to-noise ratio (Table 2 and Figure 3). Bradbury further observed in some instances that the most abundant mRNA transcripts found in a hybridoma cell line did not necessarily encode the antibody chains providing the correct specificity (e.g. pol2ser5 in Table 2). Consequently, Bradbury teaches that functional validation of all possible VH and VL combinations should be tested individually using sequence-defined recombinant antibodies (Abstract).
Regarding single domain antibodies (sdAbs) (i.e. sdAb with 3 CDRs instead of 6 CDRs), Wagner (Int J Mol Sci. 2018 Nov 2;19(11):3444) teaches that design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration because conventional antibodies utilize both VH and VL domains for antigenic recognition (page 2, last ¶). A direct CDR grafting approach was observed to produce weak antigen binders (abstract). A second step was required, in which additional affinity maturation steps by panning of synthetic phage libraries was performed generate nanobodies with sufficient antigen binding, resulting several changes in grafted CDR residues (Abstract; Figure 6B). Therefore, based on these teachings it would be unlikely that direct CDR grafting from conventional CDRs to a sdAb format without modifications would predictably generate a functional nanobody.
Based on prior art, changes to the CDR sequences of an antibody is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding the binding activity of additional productive VL chains (e.g. the two VL detected in clone F101) nor the breadth of full VH/VL sequence variability (e.g. up to 10% variance) or single domain antibodies derived therefrom that would possess the claimed anti-ROR1 antigen/antigen binding fragment target specificity without appropriate functional testing. As such, an ordinarily skilled artisan would not have recognized applicant was in possession of the entire scope of the claimed invention. Therefore, instant claims 1-2 and 4 and subsequent dependent claims 3, 6-9, 14, 19-22, 25-27, 30-32, 38, 43, 48, 50-51, 56, 60, 70-73, 75-77, 80, 84, 91-93, 111, 116, and 123-124 that do not rectify the issues with F101 clone species, sequence variance, or sdAb generation as discussed above were found not to meet the written description requirement of 35 USC 112(a).
To overcome this rejection examiner recommends to amend the claims to recite species corresponding only to those with sufficient structure and function evidence (i.e. clones 107 and 112) or to provide evidence of individual testing of antibodies with respective VH/VL or sdAb species.
Allowable Subject Matter
Anti-idiotype antibody species with sufficient written description (i.e. sequences corresponding to full complement of 6 CDRs encoded within clones F107 and F112), are free from prior art. Thus, claims 10-13 and 23-24 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647