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 .
Claims Status
Claim(s) 1, 3-8, and 10-22 is/are currently pending and presented for examination on the merits.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., Thermo Fisher Scientific, GE Healthcare, Sigma-Aldrich, Jackson ImmunoResearch, Life Technologies, Essen, Corning, Azure Biosystems), 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.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., pgs. 24-25, citations). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities:
Line 3 recites “□ (SIRP□)”, which should be “α (SIRPα)”.
Appropriate correction is required.
Duplicate Claim Warning
Applicant is advised that should claim 13 be found allowable, claim 21 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(b)
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 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.
Claim(s) 1, 3-4, and 10-22 is/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.
Claim(s) 1, 3-4, 10-22 are indefinite for reciting “a derivative thereof” (in claims 1, 14, 16, 22) as the exact meaning of the word is not known. The term “derivative'' is not one, which has a universally accepted meaning in the art nor is it one which has been adequately described in the specification. The primary deficiency in the use of this phrase is the absence of an ascertainable meaning for said term. A single exemplary species of p66 derivative lacking the p66 transmembrane domain is provided in the specification [e.g., ¶ 0033], but this is not defined as a closed group limited to the derivative disclosed. Since it is unclear how p66 is to be derivatized to yield the class of molecules referred to in the claims, a person of skill in the art cannot describe the metes and bounds of a discrete and identifiable class of molecules to these claims.
Claim(s) 15 recite(s) the term/phrase “a portion” in line 1, which renders the claim indefinite. The term “portion” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree with regards to a “portion” of a polypeptide sequence (SEQ ID NO: 1 is a p66 peptide having 618 residues), and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For the purposes of compact prosecution “portion” will be considered to mean at least 10% (e.g., 6 residues) sequence identity to the instant claimed SEQ ID NO. This rejection may be overcome by amending claim 15 to define “portion”.
Claim Rejections - 35 USC § 112(a)
Claim(s) 1, 3-8 and 10-22 is/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.
Claimed Invention
Claim(s) 1, 3-4, 13, and 20-22, are drawn to an agent (antibody or polypeptide) that binds p66.
Claim(s) 5-8 and10-12 are drawn to an antibody that binds p66.
Claim(s) 14-19 are drawn to a p66 polypeptide that binds p66.
Breadth of Claims
Anti-p66 Antibody Directed
The invention as disclosed in claim(s) 1 (and dependent claims 3-8, 10-13, 20-22) recite(s) “…an anti-p66 agent that reduces binding of p66 on the pathogen to signal regulatory protein α (SIRPα) on a phagocytic cell, where the agent (i) specifically binds to p66 (SEQ ID NO: 1),,,”. The broadest reasonable interpretation includes anti-p66 antibodies the bind p66 and reduce SIRPa binding to p66. One of ordinary skill in the art would understand that the six CDRs of an antibody or antigen binding fragment thereof (e.g., HCDR1-3 and LCDR1-3) are responsible for antigen recognition and binding characteristics. The claim(s) do/does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision VH and VL sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed function(s).
The invention as disclosed in claim(s) 5 (and dependent claims 6-8) recite(s) “…the agent is an antibody…”. One of ordinary skill in the art would understand that the six CDRs of an antibody or antigen binding fragment thereof (e.g., HCDR1-3 and LCDR1-3) are responsible for antigen recognition and binding characteristics. The claim(s) do/does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision VH and VL sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed function(s).
The invention as disclosed in claim(s) 10 (and dependent claim 11) recite(s) “…the CDR sequences of SEQ ID NO: 2 and SEQ ID NO:3, or a variant thereof…” and claim(s) 12 recite(s) “…a variable region binding sequence SEQ ID NO:2 and SEQ ID NO:3, or a variant thereof…”. The specification provides “The antibody may comprise a variant thereof, e.g. an affinity-matured variant…” [e.g., ¶ 0009], and one of ordinary skill in the art would understand affinity maturation to include alterations in the CDR(s). Therefore, the claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability in both the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to p66 antigen. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining p66 antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Anti-p66 Polypeptide Directed
The invention as disclosed in claim(s) 1 (and dependent claims 3-4, 13-22) recite(s) “…an anti-p66 agent that reduces binding of p66 on the pathogen to signal regulatory protein α (SIRPα) on a phagocytic cell, where the agent…(ii) is a p66 polypeptide or derivative thereof, wherein the effective amount of the agent is sufficient to increase phagocytosis…”. Further, the instant disclosure provides:
“p66 polypeptide In some embodiments, a subject anti-p66 agent is a p66-derived polypeptide or analogs thereof. In some embodiments, a p66-derived polypeptide is soluble, where the polypeptide lacks the p66 transmembrane domain, e.g. from about residue 143 to about residue 384 of SEQ ID NO:1. The polypeptide may comprise at least one amino acid change relative to the wild-type sequence, wherein the amino acid change increases the affinity to SIRPa…. A suitable p66 polypeptide reduces (e.g., blocks, prevents, etc.) the interaction between SIRPa and p66 protein. Such a polypeptide optionally comprises additional amino acid sequences, for example antibody Fc sequences; and the like. The polypeptides may be monomeric or multimeric, i.e. dimer, trimer, tetramer, etc., e.g. multimerized through antibody Fc region sequences.” [e.g., ¶ 0033].
The broadest reasonable interpretation includes a polypeptide(s) having one or more residue changes to the wild-type p66 polypeptide of instant SEQ ID NO: 1 which increases SIRPa binding affinity relative to wild-type p66 polypeptide. One of ordinary skill in the art would understand that the binding of a polypeptide to another polypeptide in a manner that reduces binding to a specific receptor, and the characteristics thereof (e.g., affinity), rely on the polypeptide sequence(s). The claim(s) do/does not disclose the structure (e.g., critical residues) associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision p66 derivative polypeptide(s), particularly which residue(s) are critical to bind to which region(s) of p66 in order to both reduce binding to SIRPa and increase phagocytosis, such that the obtained structure would result in the claimed function(s).
The invention as disclosed in claim(s) 15 recites “…at least a portion of SEQ ID NO: 1…” is readable to any 6 consecutive amino acids of wild-type p66 (see 112b rejection above), which for example may comprise 6 amino acids of the transmembrane domain, as being sufficient for functional p66 binding that both (1) reduces binding to SIRPa and (2) increases phagocytosis. Specifically, the claim limitations as written require only a portion of the p66 wild-type protein, but fail to specifically disclose the critical region(s) of the p66 polypeptide or derivative thereof required to perform the claimed function(s). One of ordinary skill in the art would understand that one cannot use any portion of a polypeptide (e.g., transmembrane domain only) and reasonably expect to maintain the claimed function(s).
Scope of Disclosed Species
Antibody Directed
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The anti-p66 antibody in the Applicant disclosure comprising instant SEQ ID NOs: 2-3 (see table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-p66 antibody that the applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
Polypeptide Directed
The anti-p66 polypeptide of SEQ ID NO: 1 and a soluble derivative comprising residues 143-384 of SEQ ID NO: 1 in the Applicant disclosure with 100% sequence identity represents the anti-p66 polypeptides that the applicant was in possession of at the time of filing [e.g., ¶ 0033]. It is noted that there would be support for 100% identity of the critical residues together with some percentages of identity in non-critical residues that would have been predictable, but that Applicant would need to provide evidence of determining critical residue(s) for the anti-p66 binding polypeptide and/or derivative(s) thereof.
State of the Prior Art
Antibody CDRs and Antigen Recognition
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3].
Further, at the time of filing, Ntchobo et al. (Infection and Immunity, Mar 2001, P. 1953-1956; hereinafter “Ntchobo”) taught anti-p66 antibodies were recognized in the art as a naturally occurring in both early and late-stage Lyme disease patient sera [e.g., abstract]. Ntchobo taught various IgM and IgG antibodies that bind p66 at different epitopes and with different binding characteristics [e.g., title; abstract; fig. 1; table 1]. Therefore, the prior art demonstrates that the binding of p66 is possible by various anti-p66 antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 of an anti-p66 antibody that would allow prediction of CDR residues that specifically bind to p66 antigen.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
p66 Polypeptide, SIRPa, and Phagocytosis
At the time of filing, p66 and/or derivatives thereof were not known in the art to reduce SIRPa binding and increase phagocytosis of B. burgdorferi by binding the p66 protein on B. burgdorferi. Given the above, the critical residue(s) of the p66 polypeptide and/or derivative(s) thereof that are responsible for the above claimed functions were not known at the time of filing.
After the time of filing, Tal et al. (bioRxiv [Preprint]. 2024 Apr 30: 2024.04.29.591704. doi: 10.1101/2024.04.29.591704. PMID: 38746193; PMCID: PMC11092639; hereinafter “Tal) teaches p66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by B. burgdorferi, and that p66 is necessary and sufficient to bind macrophage receptor SIRPa [e.g., title, abstract]. Tal further teaches that residues 181-187 form a loop that is required for binding SIRPa, and that residues mutating residues 184 and 186 results in loss of SIRPa binding [e.g., pgs. 3-4]. Tal does not expressly teach which residue(s) of a p66 polypeptide or derivative thereof are responsible for binding the p66 on B. burgdorferi in a manner such that the critical residues thereof cannot interact with SIRPa and phagocytosis is increased.
Thus, the critical residues of the p66 and SIRPa were not known in the art at the time of filing (earliest instance found in the prior art is Tal 2024), and the critical residue(s) of the anti-p66 polypeptide and/or derivative thereof that specifically binds to p66 on B. burgdorferi with the instant claimed functions remains unknown in the art. Therefore, one skilled in the art could not a priori make any predications regarding the critical residue(s) of the p66 polypeptide and/or derivative thereof having the claimed functions with any reasonable expectation of success nor envisage the breadth of structurally unrelated anti-p66 polypeptide variants that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds p66. Further, the critical residue(s) of an anti-p66 polypeptide having the claimed functions is required and one cannot predict which residue(s) are necessary, sufficient, and/or which residue(s) may be changed and still have the claimed function(s). Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that (1) the 6 CDRs in the antigen-binding domain of an antibody are the minimal structure that binds to a target antigen and (2) the empirically determined critical residue(s) of an anti-p66 polypeptide and/or derivative(s) thereof are the minimal structure that binds to p66 polypeptide with the claimed functions. Specifically, Applicant claim 1 (i) would need to recite the 6 CDRs (e.g., HCDR1-3 and LCDR1-3) in the antibody that bind p66 antigen, without variability in the sequences thereof, and claim 1 (ii) would need to recite either (1) the critical residue(s) of the p66 polypeptide and/or derivatives thereof that bind p66 with the claimed functions, without variability in the sequence thereof (with evidence of determining critical residues), or (2) the anti-p66 polypeptide SEQ ID NO(s) that bind p66 with the claimed functions, without variability in the sequence(s) thereof. Dependent claims 3-8 and 10-22 can overcome this rejection by amending claim 1 as described above.
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.
Claim(s) 1, 3-8, and 10-22 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 3-4, 6, 9-10, 13-14, 18, and 20 of copending Application No. 17/617,797 (reference application; hereinafter “A797”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim(s) 1, 3-8, 10-22, A797 teaches a method of inhibiting an infection of a subject by a bacterial pathogen comprising a pathogenic cd47 mimic protein (p66 is CD47 mimic protein), the method comprising administering an effective amount of an agent that reduces binding of the CD47 mimic protein on the pathogen to a SIRPa on a phagocytic cell, wherein the effective amount of the agent is sufficient to increase phagocytosis of the pathogen by a phagocytic cell [e.g., claim 1]; A797wherein the phagocytic cell is a macrophage [e.g., claim 3]; wherein the agent is an anti-CD47 mimic antibody (anti-p66 is an anti-CD47 mimic antibody) [e.g., claim 4]; wherein the agent specifically binds to the CD47 mimic protein [e.g., claim 6]; and wherein the pathogen is Borrelia burgdorferi pathogen [e.g., claims 9-10]. A797 further teaches a method of treating a subject for a Borrelia infection associated with production of a pathogenic CD47 mimic protein (p66 is a pathogenic CD47 mimic protein), the method comprising administering a therapeutically effective amount of an agent that binds to the CD47 mimic protein to a subject [e.g., claim 13]; wherein the borrelia infection is caused by Borrelia Burgdorferi [e.g., claim 14]; and wherein the agent is an antibody that binds to the CD47 mimic protein [e.g., claim 18].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Free From the Prior Art
During the course of examination, the anti-p66 antibody comprising VH and VL domains was found to be free from the prior art. Specifically, a sequence search of the prior art returned no 100% sequence identity matches to VH or HCDR1-3. Therefore the anti-p66 antibody comprising HCDR1-3 and LCDR1-3 is considered to be free from the prior art. The closest prior art for VH and VL search is provided below (CDR regions are indicated by boxes).
Alignment of anti-p66 VH and VL domains (SEQ ID NOs: 2-3, respectively) with WO2020227447-A1 (Anti-GPC2 single chain antibody GPC2.19, SEQ ID 21):
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Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643