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 ACTIONChange in Examiner
1. This application has been transferred to different Primary Examiner. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Lynn Bristol, Group Art Unit 1643.
Withdrawal of Finality of the Rejection
2. The finality of the rejection is withdrawn in view of new grounds for objection and rejection.
Status of the Claims
3. Claims 1-20 are the original claims filed 12/31/2020. In the Reply of 9/26/2023, no changes are made to the claims. In the Response of 2/5/2024, Claims 1 and 10-11 are amended and claims 12, 14 and 16-20 are canceled. In the Response of 8/20/2024, Claims 1 and 11 are amended. In the Response of 2/24/2025, Claims 1 and 7 are amended and new claims 21-22 are added. In the Response of 7/11/2025, Claims 1 and 10 are amended, Claims 9 and 21-22 are canceled, and new Claims 23-29 are added. In the Response of 1/13/2026, Claims 1 and 23 are amended.
Claims 1-8, 10-11, 13, 15, and 23-29 are pending.
Claims 3 and 15 are withdrawn.
Claims 1-2, 4-8, 10-11, 13 and 23-29 are the claims under examination.
Priority
4. USAN 17/257,391, filed 12/31/2020, and having 2 RCE-type filing therein, is a National Stage entry of PCT/US2019/040336, International Filing Date: 07/02/2019,
PCT/US2019/040336 Claims Priority from Provisional Application 62/693,125, filed 07/02/2018.
Information Disclosure Statement
5. As of 7/29/2026, a total of seven (7) IDS are filed: 12/31/2020; 3/3/2021; 3/3/2021; 3/3/2021; 3/3/2021; 2/24/2025; and 5/26/2026. The corresponding initialed and dated 1449 form is considered and of record.
6. The listing of references in the specification in Tables 2, 3C, 5, 6, 7, 8, 9, 10, 11, 12, and 13 are not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claim 23 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn. Claim 23(a)(i) is amended to comport with claim 23(b)(i).
Claim Rejections - 35 USC § 112(a)
8. The rejection of Claims 1-2, 4-8, 10-11 and 13 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 is withdrawn. Claim 1 is amended to delete the species for transferrin receptor, Ly6E, CD98, Integrin aV33, Integrin a6p4, Integrin a5p1, integrin αV, heat shock proteins, TNFRSF10B, and VCAM-1 (CD 106) from the list of tumor antigens and CD2 from the list of immune cell markers.
9. The rejection of Claims 23-29 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 is withdrawn. Claim 23 is amended to delete CD20 from the list of B cell antigens.
New Grounds for Objections
Drawings
10. The drawing sheets for Figures 11-13 are objected to because the use of the term “BiTE”, which is a trade name or a mark used in commerce, has been noted. 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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
11. The disclosure is objected to because of the following informalities:
a) The use of the term BiTE, ExPASy, Oncomine, PMAP, DARPin, Affibody, Pronectin, 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.
b) The specification contains peptide sequences that are > 4 amino acids in length that pursuant to 37 CFR 1.821-1.825 are required to be identified by SEQ ID NO. See [00184].
Appropriate correction is required.
Claim Objections
12. Claims 4-6, 8, 26 and 28 are objected to because of the following informalities:
a) Amend claim 4 to recite “wherein the first immune cell engaging domain[s] and the second immune cell engaging domain” in order to clarify the immune cell engaging domain partners.
b) Amend claim 5 to recite “the immune cell selection moiety
c) Amend claim 6 to recite “wherein the immune cell selection moiety
d) Amend claim 8 to recite “wherein the first immune cell engaging domain[s] and the second immune cell engaging domain” in order to clarify the immune cell engaging domain partners.
e) Amend claim 26 to recite “the immune cell selection moiety
f) Amend claim 28 to recite “wherein the first immune cell engaging domain[s] and the second immune cell engaging domain” in order to clarify the immune cell engaging domain partners.
Appropriate correction is required.
New Grounds for Rejection
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.
13. Claims 1-2, 4-8, 10-11, 13 and 23-29 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 1-2, 4-8, 10-11, 13 and 23-29 are indefinite for the phrase “capable of”. The specification does not provide a definition for the phrase. The phrase implies that some undefined structure or condition is what predicates whether the function or activity associated with a claimed capability does or does not occur. Capacity and capability suggest that the function or activity may sometimes occur but not always, and what determines the degree or amount of the function or activity is not definite by the use of the phrase.
b) Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “inert” in claims 1-2, 4-8, 10-11, 13 and 23-29 is used by the claim to mean “reduced affinity”, while the accepted meaning is devoid of active chemical properties (www.merriam-webster.com/dictionary/inert). The term is indefinite because the specification does not clearly redefine the term.
c) Claims 1-2, 4-8, 10-11, and 13 recite the limitation "ii. a first immune cell engaging domain capable of immune engaging activity when binding a second immune cell engaging domain, wherein the second immune cell engaging domain is not part of the first component," in Claim 1(a)(ii) and recite the limitation “ii. a second immune cell engaging domain capable of immune cell engaging activity when binding the first immune cell engaging domain,” in Claim 1(b)(ii). It is neither clear nor concise whether a second immune cell engaging domain in Claim 1(a)(ii) is the same as the second immune cell engaging domain in Claim 1(b)(ii).
d) 23-29 recite the limitation "ii. a first immune cell engaging domain capable of immune engaging activity when binding a second immune cell engaging domain, wherein the second immune cell engaging domain is not part of the first component," in Claim 23(a)(ii) and recite the limitation “ii. a second immune cell engaging domain capable of immune cell engaging activity when binding the first immune cell engaging domain,” in Claim 23(b)(ii). It is neither clear nor concise whether a second immune cell engaging domain in Claim 23(a)(ii) is the same as the second immune cell engaging domain in Claim 23(b)(ii).
e) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 5 recites the broad recitation “a T cell”, and the claim also recites “a γδ T cell” and “a natural killer T cell (NKT cells)”, which is the narrower statement of the range/limitation.
In the present instance, claim 23(b)(i) recites the broad recitation “a T cell”, and the claim also recites “a γδ T cell” and “a natural killer T cell (NKT cells)”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
f) Claim 11 recites the limitation " melanocyte stimulating hormone receptor (MSH receptor) or folate hydroxylase (FOLH1)". There is insufficient antecedent basis for this limitation in the claim in depending from claim 1. Claim 1 recites “chosen from” language for what is presumed to be closed language and where neither species of solid tumor target antigen is claimed.
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.
14. Claims 5 and 23 are 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.
Claim 5 recites “or an engineered immune cell” as the target of the immune cell selection moiety of claim 1. Claim 1 is closed for the immune cell markers that the immune cell selection moiety targets, namely, “CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and γδTCR.” Thus, it is unclear whether the engineered immune cell expresses CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and/or γδTCR.
Claim 23 recites “or an engineered immune cell” as the target of the immune cell selection moiety of claim 23. Claim 23 is closed for the immune cell markers that the immune cell selection moiety targets, namely, “CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and γδTCR.” Thus, it is unclear whether the engineered immune cell expresses CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and/or γδTCR.
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.
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
15. Claims 1-2, 4-8, 10-11, 13 and 23-29 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 interpretation
Claims 1-2, 4-8, 10-11, and 13 are infinite in scope for the combination of elements comprising each of 1st, 2nd, 3rd and 4th components (antibody tumor-targeting assembly complexes (ATTACs)) for any agent to treat any solid tumor in any patient:
1st component: anti-tumor targeting moiety comprising an anti-tumor antigen antibody or α-MSH or folic acid; and a first immune cell engaging domain comprising either a VH or VL;
2nd component: immune cell selection moiety comprising an anti- CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and/or γδ TCR antibody; and a second immune cell engaging domain comprising either a VH or VL where when the 1st immune cell engaging domain is VH the 2nd immune cell engaging domain is VL and vice versa;
3rd component: inert binding partner bound to the 1st and/or 2nd immune cell engaging domain (VH or VL) that prevents association of the VH/VL pairing;
4th component: cleavage site located between inert binding partner and the 1st and/or 2nd immune cell engaging domain (VH or VL) that allows association of the VH/VL pairing upon cleavage.
Claims 23-29 are infinite in scope for the combination of elements comprising each of 1st, 2nd, 3rd and 4th components (antibody tumor-targeting assembly complexes (ATTACs)) for any agent to treat any B cell malignancy in any patient:
1st component: B cell malignancy targeting moiety comprising an anti-BCMA or CD19 antibody; and a first immune cell engaging domain comprising either a VH or VL;
2nd component: immune cell selection moiety comprising an anti- CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and/or γδ TCR antibody that targets a T cell, a macrophage, a natural killer cell, a neutrophil, an eosinophil, a basophil, a γδ T cell, a natural killer T cell (NKT cell), or an engineered immune cell; and a second immune cell engaging domain comprising either a VH or VL where when the 1st immune cell engaging domain is VH the 2nd immune cell engaging domain is VL and vice versa;
3rd component: inert binding partner bound to the 1st and/or 2nd immune cell engaging domain (VH or VL) that prevents association of the VH/VL pairing;
4th component: cleavage site located between inert binding partner and the 1st and/or 2nd immune cell engaging domain (VH or VL) that allows association of the VH/VL pairing upon cleavage.
“treat”/ “treatment”: the specification is unequivocal in teaching that the term “treat” is inclusive of both prophylaxis and therapy at
[0225] In some embodiments, treatment is pre-emptive or prophylactic.
The POSA could reasonably conclude that the agent is both therapeutic and prophylactic.
“immune cell engaging domain”: examples of targets that bind the immune cell engaging domain are taught at
[0015] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a natural killer cell. In some embodiments, the immune cell selection moiety targets CD2 or CD56. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding NKG2D, CD16, NKp30, NKp44, NKp46 or DNAM.
[0016] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a macrophage. In some embodiments, the immune cell selection moiety targets CD14, CD11b, or CD40. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding CD89 (Fc alpha receptor 1), CD64 (Fc gamma receptor 1), CD32 (Fc gamma receptor 2A) or CD16a (Fc gamma receptor 3A).
[0017] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a neutrophil. In some embodiments, the immune cell selection moiety targets CD15. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding CD89 (FcαR1), FcγRI (CD64), FcγRIIA (CD32), FcγRIIIA (CD16a), CD11b (CR3, αMβ2), TLR2, TLR4, CLEC7A (Dectin1), formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), or formyl peptide receptor 3 (FPR3).
[0018] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets an eosinophil. In some embodiments, the immune cell selection moiety targets CD193, Siglec-8, or EMR1. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding CD89 (Fc alpha receptor 1), FcεRI, FcγRI (CD64), FcγRIIA (CD32), FcγRIIIB (CD16b), or TLR4.
[0019] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a basophil. In some embodiments, the immune cell selection moiety targets 2D7, CD203c, or FcεRIα. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding CD89 (Fc alpha receptor 1) or FcεRI.
[0020] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a γδ T cell. In some embodiments, the immune cell selection moiety targets γδ TCR. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding γδ TCR, NKG2D, CD3 Complex (CD3ε, CD3γ, CD3δ, CD3ζ, CD3η), 4-1BB, DNAM-1, or TLRs (TLR2, TLR6).
[0021] In some embodiments, the immune cell selection moiety capable of selectively targeting an immune cell selectively targets a natural killer T cell. In some embodiments, the immune cell selection moiety targets Vα24 or CD56. In some embodiments, the immune cell engaging domains, when bound to each other, are capable of binding αβTCR, NKG2D, CD3 Complex (CD3ε, CD3γ, CD3δ, CD3ζ, CD3η), 4-1BB, or IL-12R.
The POSA could reasonably conclude that the immune cell selection moiety and the immune cell engaging domains are NOT overlapping with respect to the antigen to which they are directed. Notably, with the exception of Claims 8 and 28 drawn to CD3 or TCR, none of the claims are limited to the immune cell selection moiety. The POSA could reasonably conclude that the genus of immune cell selection moiety is infinite in scope and well beyond what is taught in the specification.
“inert binding partner”: the specification defines the binding partner by function without structure:
[0034] In some embodiments, at least one inert binding partner specifically binds the immune cell engaging domain. In some embodiments, at least one inert binding partner is a VH or VL domain.
[0199] In some embodiments, the inert binding partner is a VH or VL that cannot specifically bind an antigen when paired with its corresponding VL or VH of the immune cell engaging domain because of one or more mutations made in the inert binding partner to inhibit binding to the target antigen. In some embodiments, the VH or VL of the inert binding partner may differ by one or more amino acids from a VH or VL specific for an immune cell antigen. In other words, one or more mutations may be made to a VH or VL specific for a target immune cell antigen to generate an inert binding partner.
[0200] These mutations may be, for example, a substitution, insertion, or deletion in the polypeptide sequence of a VH or VL specific for an immune cell antigen to generate an inert binding partner. In some embodiments, the mutation in a VH or VL specific for an immune cell antigen may be made within CDR1, CDR2, or CDR3 to generate an inert binding partner. In some embodiments, an VH or VL used as an inert binding partner may retain the ability to pair with an immune cell engaging domain, but the resulting paired VH/VL domains have reduced binding to the immune cell antigen. In some embodiments, an inert binding partner has normal affinity to bind its corresponding immune cell engaging domain, but the paired VH/VL has lower binding affinity for the immune cell antigen compared to a paired VH/VL that does not comprise the mutation of the inert binding partner. For example, this lower affinity may be a 20-fold, 100-fold, or 1000-fold lower binding to an immune cell antigen.
The POSA could reasonably conclude that the genus of inert binding partners is infinite in scope and well beyond what is taught in the specification.
The POSA could reasonably conclude that the term “inert” is not consistent with the medical dictionary definition for the term, namely, devoid of active chemical properties (www.merriam-webster.com/dictionary/inert). The specification requires the binding partner to have some affinity if not reduced for the corresponding VH and VL domain in order to block the VH/VL pairwise formation.
The claimed invention encompasses a genus of therapeutic and prophylactic antibody solid tumor-targeting ATTACs (Claim 1) or antibody B cell malignancy-targeting ATTACs (Claim 23). Because applicant seeks patent protection for all such ATTACs, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
All of the claims encompass ATTACs comprising any VH and any VL domain for each of the 1st, 2nd, and 3rd components in which the variable domain structures including the complementarity determining regions (CDRs) for each component are infinite in scope and defined only by function. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
It is well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses ATTAC constructs in Table 1B comprising SEQ ID NOS: 165-172.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus of ATTACs based on the limited disclosure in the specification.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has provided a common structure for the ATTAC defined by generic function and that is not sufficient to visualize the genus of all possible variants.
(a) One of ordinary skill in the art could not predict which of all of the VH/VL domains functioned similarly for each of the 1st and 2nd components despite the prior art in Tables 2-3, 4C, 5, 6, 7, 8, 9, 10, 11, 12, and 13. It is unclear what structural features for any one of these antibodies can be engineered into the ATTAC that maintains binding affinity and stability.
Therapeutic antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of claimed target antigens are known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
(b) One of ordinary skill in the art could not predict which of all inert binding partners (masking moiety) function similarly for each of the 3rd components. The complexities of masking antibody moieties involve affinity balancing incomplete target inhibition, on/off rates, and structural instability. Key challenges include fine-tuning the mask's binding affinity, optimizing linker length, and preventing unwanted immunogenicity (Donaldson et al (Cancer Biol Ther. 2009 Nov 7;8(22):2147–2152). Applicants have not shown themselves to be in possession of the universe of inert binding partners in view of the instant claim scope.
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the ATTAC of the genus for reliably assigning different antibody structures based on limited sequence data for constructs, which would support the premise that the inventors possessed the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
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 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.
17. Claim(s) 1, 4-8, 10, 13, 23, 25-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lowman et al. (USPN 11161906 or US 20210238291; priority filing date 7/25/2014 (PTO 892)).
The claim interpretation of the pending generic claims is set forth above under the 112, 1st written description rejection (section 16).
Claim(s) 1-2, 4-8, 10-11, 13 and 23-29 are prima facie obvious over Lowman.
As regards Claims 1 and 23, Lowman teaches a multispecific activatable antibody that comprises: at least a first antibody or an antigen binding fragment thereof (AB1) that specifically binds a first target or epitope; a second antibody or an antigen binding fragment thereof (AB2) that specifically binds a second target or epitope; at least a first masking moiety (MM1) that inhibits the binding of the AB1 to the first target or epitope; and at least a first cleavable moiety (CM1) coupled to the AB1 and coupled to the MM1, wherein the CM1 is a substrate for a protease, wherein the CM1 is between the AB1 and the MM1, wherein the AB2 is attached to an N-terminus or a C-terminus of a heavy chain or a light chain of the AB1, wherein AB1 is a targeting antibody or antigen-binding fragment thereof that specifically binds the first target or epitope present on the surface of a tumor cell or other cell type associated with disease and AB2 is an immune cell engaging antibody or antigen-binding fragment thereof that specifically binds the second target or epitope present on the surface of an immune effector cell, and wherein the protease cleaves the CM1 in the multispecific activatable antibody when the multispecific activatable antibody is exposed to the protease. The structure of Lowman teaches the agent of the instant generic claims 1 and 23 where the 1st component targeting a tumor corresponds to AB1, the 2nd component targeting an immune cell engaging domain or an immune selection moiety corresponds to at least an AB2, the 3rd component comprising the inert binding partner corresponds to the masking moiety (MM1/MM2), and the 4th component for the protease cleavage site corresponds to the cleavable moiety (CM1/CM2).
AS regards Claims 1 and 23, Lowman teaches targeting tumor antigens EGFR, erbB2, EpCAM, (Claim 1) and CD19 (Claim 23); and targeting the immune effector cell expressing CD3 (immune engager domain) and CD4 and CD8 (immune cell selection moiety).
AS regards claims 4-8, 10 and 25-28, Lowman teaches the activated multispecific agent binds to the respective antigen on the tumor (solid) or immune cell as for example:
In some embodiments, multispecific antibodies or fragments thereof of the disclosure include at least (i) a T-cell engaging antibody or fragment thereof that includes a first antibody or antigen-binding fragment thereof (AB1) that binds a first, T-cell engaging target that is a surface antigen on a T cell and (ii) a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds a second target. In some embodiments, the first and second targets are the same antigen. In some embodiments, the first and second targets are different antigens. In some embodiments, the first and second targets are different epitopes on the same antigen. In some embodiments, the T-cell engaging antibody or fragment thereof is attached the N-terminus of the heavy chain of the target-specific antibody. In some embodiments, the T-cell engaging antibody or fragment thereof is attached the C-terminus of the heavy chain of the target-specific antibody. In some embodiments, the T-cell engaging antibody or fragment thereof is attached the N-terminus of the light chain of the target-specific antibody. In some embodiments, the T-cell engaging antibody or fragment thereof is attached the C-terminus of the light chain of the target-specific antibody. In some embodiments, the multispecific antibody comprises T-cell engaging antibodies or fragments thereof attached to a combination of one or more N-termini and/or one or more C-termini of the multispecific antibody. The disclosure also includes multispecific antibodies that comprise another immune effector cell engaging antibody or fragment thereof, such as one that binds a surface antigen of a natural killer (NK) cell, a mononuclear cell, such as a myeloid mononuclear cell, a macrophage, and/or other immune effector cells.
In some embodiments, the cleavable moiety (CM) of the multispecific activatable antibody includes an amino acid sequence that can serve as a substrate for a protease, usually an extracellular protease. The CM may be selected based on a protease that is co-localized in tissue with the desired target of at least one AB of the multispecific activatable antibody. A variety of different conditions are known in which a target of interest is co-localized with a protease, where the substrate of the protease is known in the art. In the example of cancer, the target tissue can be a cancerous tissue, particularly cancerous tissue of a solid tumor. There are reports in the literature of increased levels of proteases having known substrates in a number of cancers, e.g., solid tumors. See, e.g., La Rocca et al, (2004) British J. of Cancer 90(7): 1414-1421. Non-liming examples of disease include: all types of cancers (breast, lung, colorectal, prostate, melanomas, head and neck, pancreatic, etc.), rheumatoid arthritis, Crohn's disuse, SLE, cardiovascular damage, ischemia, etc. For example, indications would include leukemias, including T-cell acute lymphoblastic leukemia (T-ALL), lymphoblastic diseases including multiple myeloma, and solid tumors, including lung, colorectal, prostate, pancreatic and breast, including triple negative breast cancer. For example, indications include bone disease or metastasis in cancer, regardless of primary tumor origin; breast cancer, including by way of non-limiting example, ER/PR+ breast cancer, Her2+ breast cancer, triple-negative breast cancer; colorectal cancer; endometrial cancer; gastric cancer; glioblastoma; head and neck cancer, such as esophageal cancer; lung cancer, such as by way of non-limiting example, non-small cell lung cancer; multiple myeloma ovarian cancer; pancreatic cancer; prostate cancer; sarcoma, such as osteosarcoma; renal cancer, such as by way of nonlimiting example, renal cell carcinoma; and/or skin cancer, such as by way of nonlimiting example, squamous cell cancer, basal cell carcinoma, or melanoma. In some embodiments, the cancer is a squamous cell cancer. In some embodiments, the cancer is a skin squamous cell carcinoma. In some embodiments, the cancer is an esophageal squamous cell carcinoma. In some embodiments, the cancer is a head and neck squamous cell carcinoma. In some embodiments, the cancer is a lung squamous cell carcinoma.
As regards claims 13 and 29, Lowman teaches working examples of protease cleavage essential to the mulitspecific activatable antibody at:
FIG. 23A demonstrates that EGFR-dependent activation, as determined by CD69 induction of primary T cells co-cultured with EGFR-expressing SW480 cells, by multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N was attenuated compared to EGFR-dependent activation exhibited by multispecific antibody C225v5-OKT3m-H-N. The figure also indicates that EGFR-dependent activation by the multispecific activatable antibody was fully restored upon protease cleavage of the multispecific activatable antibody by matriptase. OKT3, anti-EGFR C225v5, and Synagis IgGlisotype control antibodies exhibited negligible activation of T-cells.
FIG. 23B demonstrates that EGFR-dependent lysis of SW480 cells by multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N was attenuated compared to EGFR-dependent cytotoxicity exhibited by multispecific antibody C225v5-OKT3m-H-N. The figure also indicates that EGFR-dependent cytotoxicity by the multispecific activatable antibody was fully restored upon protease cleavage of the multispecific activatable antibody by matriptase. C225v5 and OKT3 and Synagis IgG1 isotype control antibodies exhibited negligible cytotoxicity.
Lowman teaches the activatable multispecific antibodies are stable in circulation, activated at intended sites of therapy and/or diagnosis but not in normal, i.e., healthy tissue, and, when activated, exhibit binding to a target that is at least comparable to the corresponding, unmodified multispecific antibody. The POSA would find sufficient motivation to make from the disclosure much less the working examples in Lowman the instant claimed multispecific activatable antibody agents along with a reasonable assurance of success based on the predictability of the art.
18. Claim(s) 2 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lowman et al. (USPN 11161906 or US 20210238291; priority filing date 7/25/2014) as applied claims 1 and 23 above, and further in view of Baeuerle et al (WO2017156178; published 2017-09-14 (PTO 892)).
Claims 2 and 24 are prima facie obvious over Lowman in view of Baeuerle.
Baeuerle teaches a structure for an activatable antibody agent as disclosed in Lowman as
1st component: anti-tumor targeting moiety comprising an anti-tumor antigen antibody (EGFR); and a first immune cell engaging domain comprising either a VH or VL (CD3);
2nd component: a second immune cell engaging domain comprising either a VH or VL (CD3) where when the 1st immune cell engaging domain is VH the 2nd immune cell engaging domain is VL and vice versa;
3rd component: inert binding partner bound to the 1st and/or 2nd immune cell engaging domain (VH or VL) that prevents association of the VH/VL pairing;
4th component: cleavage site located between inert binding partner and the 1st and/or 2nd immune cell engaging domain (VH or VL) that allows association of the VH/VL pairing upon cleavage.
AS regards claims 2 and 24, Baeuerle teaches the components are separated and not covalently bound as in Figures 28 and 30 for targeting domains that upon cleavage form the construct agent.
Lowman teaches the activatable multispecific antibodies are stable in circulation, activated at intended sites of therapy and/or diagnosis but not in normal, i.e., healthy tissue, and, when activated, exhibit binding to a target that is at least comparable to the corresponding, unmodified multispecific antibody which along with Baeuerle are just as effective in non-colavet versus covalent form. The POSA would find sufficient motivation to make from the disclosure much less the working examples in Lowman in view of Baeuerle the instant claimed multispecific activatable antibody agents along with a reasonable assurance of success based on the predictability of the art.
Double Patenting
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.
19. Claims 1-2, 4-8, 10-11, 13 and 23-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 31 of copending Application No. 17/608,101 (reference application US 20220323600). The reference is not afforded safe harbor protection under 35 USC 121 because it shares no continuity nor a restriction/ speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the agent for each of the claim sets comprises an ATTAC comprising each of 1st, 2nd, 3rd and 4th components:
1st component: anti-tumor targeting moiety comprising an anti-tumor antigen antibody or α-MSH or folic acid; and a first immune cell engaging domain comprising either a VH or VL;
2nd component: immune cell selection moiety comprising an anti- CD8, CD4, CD11b, T cell receptor Vα24, 2D7, CD203c, Siglec-8, EMR1, and/or γδ TCR antibody; and a second immune cell engaging domain comprising either a VH or VL where when the 1st immune cell engaging domain is VH the 2nd immune cell engaging domain is VL and vice versa;
3rd component: inert binding partner bound to the 1st and/or 2nd immune cell engaging domain (VH or VL) that prevents association of the VH/VL pairing;
4th component: cleavage site located between inert binding partner and the 1st and/or 2nd immune cell engaging domain (VH or VL) that allows association of the VH/VL pairing upon cleavage.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
20. No claims are allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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