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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/02/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification (last page) is 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 in IDS, or by the examiner on form PTO-892, they have not been considered.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The use of the term VivaspinTM, 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.
While the Examiner has made every attempt to check the Specification for trade mark compliance, Applicant is required to carefully check the entire Specification for any and all issues regarding trade mark use compliance.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency - Sequences appearing in the specification (see page 48, for instance) are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Status of the Claims
Claims 1-26 and 32-36 are pending in this application. Claims 27-31 have been canceled by Applicant.
Examiner Notes
Claims 3, 5-7, 16-17, 20, and 24-25 are free of the prior art, however, they stand rejected and/or objected over formal matters.
Acronyms used herein:
autoimmune thrombocytopenic purpura (ATP)
idiopathic thrombocytopenic purpura (ITP)
thrombotic thrombocytopenic purpura (TTP)
Claim Interpretation
The terms “hooking head”, “spacer”, and “linker arm” are not specifically defined in the specification. Therefore, unless otherwise defined in each claim, the terms will be given the broadest reasonable interpretation, and each of “hooking head”, “spacer”, and “linker arm” will be understood as encompassing any linking bond or group connecting the antibody and the protease of the claimed antibody-enzyme conjugate.
Claim Objections
Claims 5, 7, 9, 11-18, 20, and 34 is objected to because of the following informalities:
Claims 5 and 11 some variables under the definition of R9 are separated by commas ‘,’ while others are separated by semicolons ‘;’ – please revise for consistency.
Claims 7, 9, and 12-18 appear to have period after one of the definitions of Rb (
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) – please change to a comma or correct the size of the comma for consistency if it is already a comma.
Claims 9, 12-18 recite several repeated definitions of variables, such as m, p, q, r, Rc, R3, R4, and/or R5, etc. Remove every repeated definition and/ or consolidate definitions to eliminate redundancy. See 112(b) for broad/narrow limitation issues.
Claim 20 also contains repeated definitions - consolidate to avoid redundancy. The claim should also read: “The conjugate according to claim 1, of Formula (A), (B), or (C)” – Currently, the claim reads “The conjugate according to claim 1, of Formula (A), (B), and (C)” – see page 46, 3rd to last line.
Further regarding claim 20, the claim reads: “wherein the portion constituted by the spacer and the linker arm is represented by one of . . .” Claim should read: “wherein the Spacer-Linker Arm portion corresponds to one of Formulae III or IV” or something to that effect, for clarity.
Claim 34 is missing an “and”, “or”, or “and/ or” before “drug-induced thrombocytopenias.”
Appropriate correction is required.
Claims 3, 6, and 24-25 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.
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.
Claims 5, 7, 9, 11-18, and 20 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 5 is indefinite because the claim states the linker arm can be
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. It is unclear if Applicant intends for the groups coming off R10 and the methyne to be methyl groups, or if Applicant intends for these groups to indicate additional divalent connection points, as in
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.
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 instant case:
Claim 7 recites the broad recitation “A is the residue of a phenyl or a pyridyl; W is …” (see line 8 to end of claim 7) – as an initial matter, there is no variables A, W, etc. in the claim, therefore, it is unclear why these definitions are recited in this claim. Furthermore, the claim also recites, “wherein the hooking head is a compound of Formula (Ib) or (Ib’)”, which is the narrower statement of the range/limitation.
Claims 9, 12-18 recite two sets of definitions for m, p, q, r, u, etc. one of which is broader than the other. See below, for example:
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and
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check all variables in these claims for compliance in these claims. Remove repeated definitions.
Claim 14 states: “
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” and “
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” then recites “
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” which is the narrower limitation.
Claim 15 recited the broad limitations “
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” and “
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” (page 30, line 12-13); and also recites: “
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” and “
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“(page 29, line 3 and 6), which are the narrower statement of the range/limitation. Claim 15 has many issues with broad/ narrow definitions and repeated definitions – see definitions for q, r, p, R3, R4, R5 etc. – consolidate and remove repeated definitions of all variables with issues in this claim.
Claim 16 recites the broad limitations “
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is …” (page 35 of claims); and also specifically defines
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in page 33 of the claims, which are the narrow limitations. Similar to claim 15, claim 16 has many repeated definitions and many broad/narrow issues. See definitions of q, r, p, R3, R4, R5 etc. – consolidate and remove repeated definitions of all variables with issues in this claim.
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.
Further regarding claims 9, 12-18, and 20, the claims state: “with the exception of the following compounds:” (then list 2 compounds). It is unclear what these compounds refer to. Does Applicant intend “wherein
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is not either of [compounds listed]” or does Applicant intend “wherein X1 is not either of [compounds listed]”?
Further regarding claims 15 and 17, the claims contain a definition for
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, however, this variable is not present in any of the structures presented in the claim. It is unclear if a structure is missing or if the definitions were included by mistake.
Claim Rejections - 35 USC § 103
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.
Claims 1-2, 4, 21-23, 26, and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO 2020/257998 A1 – Int. Filing Date: 06/24/2019) (“Zhao”); in view of Kjellman et al. (WO 2016/128559 A1 – cited in IDS) (“Kjellman”); and Delgado et al. (Hematologia, 2002, 87, 215-216) (“Delgado”).
Regarding instant claim 1, Zhao teaches antibody-drug conjugates (ADC) consist of a monoclonal antibody (mAb) and a cytotoxic drug via specialized linking which allows for delivery of cytotoxic agents to target cells (page 1). Zhao discloses the ADC a159 below, for example (page 362, bottom) – reading on a conjugate comprising an antibody. Zhao discloses their antibody may be rituximab (anti-CD20), among many others (page 174, line 4). Zhao also teaches their therapeutics may be used for the treatment of autoimmune diseases, specifically disclosing autoimmune thrombocytopenic purpura (ATP) or idiopathic ITP (page 195, lines 16 and 35), among other conditions, depending on the antibody used to target specific cells.
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While Zhao does not teach their ADC comprising a protease specific for the IgG hinge region, the teachings of Kjellman and Delgado are relied upon for these disclosures.
Kjellman teaches IdeS as an IgG cysteine protease which has in vivo utility as a therapeutic agent for diseases that are wholly or partly mediated by IgG (pages 1-2). Kjellman teaches subject receiving IdeS will often respond to it by producing antibodies specific for IdeS (“anti-drug antibodies” or ADA), which may result in reduced efficacy of IdeS treatment and there may be harmful complications, such as hyperinflammation (page 2). Kjellman teaches their IgG cysteine proteases can effective for the treatment of autoimmune diseases (Kjellman’s claim 12; Table D, page 32), including thrombotic thrombocytopenic purpura (TTP) and ITP.
Delgado teaches several authors have recently reported impressive results with anti-CD20 monoclonal antibody (rituximab) therapy in refractory ITP, with a complete response rate of 20% and an overall response rate of 52%; and reports on four patients who were treated for refractory ITP with rituximab, demonstrating the possible usefulness of such therapy in this clinical setting (page 1, col. 1).
Therefore, it would have been prima facia obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare a conjugate consisting of an antibody fragment, such as rituximab (anti-CD20), and an IgG cysteine protease, like IdeS, for the treatment of conditions which are wholly or partly mediated by IgG, as taught by Zhao in view of Kjellman and Delgado. One of ordinary skill would have been motivated to do so because Zhao discloses their ADCs for targeted drug delivery, which avoids systematic exposure to toxic therapeutics, and teaches their ADCs may be linked to antibodies such as rituximab, and that their ADCs may be useful for the treatment of autoimmune diseases, such as ATP or ITP. One of ordinary skill would have been further motivated because Kjellman teaches IdeS as an IgG cysteine protease which has in vivo utility as a therapeutic agent for diseases mediated by IgG, including ATP, TTP, or ITP, but may cause reduced treatment efficacy and hyperinflammation if administered on its own – thus motivating one of ordinary skill to prepare an antibody-enzyme conjugate and avoid systemic exposure. One would have been further motivated because Delgado teaches TP patients responded to rituximab therapy. One having ordinary skill in the art would have had a reasonable expectation of success because Zhao discloses their ADCs and methods of making them and Kjellman discloses IdeS and its therapeutic utility. Applicant is advised, a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR,550 U.S. at 421, 82 USPQ2d at 1397.
Regarding claims 2 and 4, Zhao’s compound reads on Formula A as follows:
“Hooking head” is
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; “spacer” may be a bond (reading on claim 4) or
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; and the “linker arm” may be
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.
Regarding claim 21, Zhao teaches the antibodies in their ADCs may be Fab fragments, F(ab)’ fragments, or F(ab)2’ fragments (page 15, last 3 lines).
Regarding claim 22-23, Kjellman teaches IdeS and IdeZ (page 3). Kjellman discloses cleavage of IgG1 and IgG2 (page 61, line 21).
Regarding claim 26, Zhao discloses pharmaceutical compositions comprising their ADCs (page 202, line 8; and Zhao’s claim 15). Kjellman also discloses pharmaceutical compositions (page 29, line 4; and Kjellman’s claim 9).
Regarding claims 32-34, Kjellman discloses treatment of several disease induced by autoantibodies and wholly or in part by IgGs (see Kjellman’s claim 12, and Table D, pages 33-34), including TTP or idiopathic TP. Zhao teaches their ADCs are useful for treating autoimmune TP (reading on immune TP) (page 195, lines 16).
Claims 1, 8-15, 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO 2020/257998 A1 – Int. Filing Date: 06/24/2019) (“Zhao”); in view of Kjellman et al. (WO 2016/128559 A1 – cited in IDS) (“Kjellman”); and Delgado et al. (Hematologia, 2002, 87, 215-216) (“Delgado”); as applied to claims 1-2, 4, 21-23, 26, and 32-34; further in view of Juen et al. (WO 2022/018371 A1 – Int. Filing Date: July 19th, 2021 – Cited in IDS – Used US 2023/0277678 A1 as English translation of the WIPO document) (“Juen”).
The Juen reference shares a common Applicant with the instant invention.
The teachings of Zhao, Kjellman, and Delgado are disclosed above and incorporated herein.
Zhao teaches a linkage containing a triazole in the conjugates can be achieved by reaction of an alkyne and an azido group through a known click-reaction (page 166, line 10-13).
While Zhao in view of Kjellman and Delgado do not teach the instantly claimed antibody-protease conjugates; the teachings of Juen are relied upon for these disclosures.
Juen discloses their compounds of Formula I to be conjugated to a protein via at least two disulfide bonds (abstract). Juen discloses the compounds 20, 39, and 41 below, for instance (see [0348], [0671], [0699], [0815] of US Application doc.). Juen discloses click reactions are well known to a person of ordinary skill in the art ([0131]). Juen also teaches the antibody fragment can be bound to their compounds by a substitution reaction of the bromides in 20, 39, and 41 below to form disulfide bonds ([0137]). Juen’s compounds read on instant Formulae B and C when the “hooking head” is
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, wherein the bromides can be substituted to for they disulfide bonds once the antibody is bound. This group corresponds to instant A being phenyl or pyridine; Y being -C(O)-; X1 being
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, wherein Z is -NH-; and W is –(CH2CH2O)q-(CH2)r-R5, wherein R5 is
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,
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, or
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Therefore, regarding instant claims 1, 8-15, 18-19; it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare any of the instant conjugates of Formula B or C in view of (Zhao, Kjellman, and Delgado) further in view of Juen. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because (Zhao, Kjellman, and Delgado) disclose their antibody-protease conjugates of rituximab-IdeS, with Zhao specifically disclosing methods of making their ADCs, and teaching that known click reactions can be used to prepare triazoles from alkynyl and azide coupling partners; further because Juen teaches their compounds for use in the preparation of ADCs, comprising bromide leaving groups to facilitate substitution reactions to form disulfide bonds with antibodies, and alkyne moieties to facilitate click chemistry and allow connection of the protease portion of the conjugate. Applicant is reminded that a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Furthermore, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Therefore, the substitution of Zhao’s ‘linker’ (hooking head-spacer-linker arm) for Juen’s is obvious to one of ordinary skill in the art. See MPEP 2144.06 (II).
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO 2020/257998 A1 – Int. Filing Date: 06/24/2019) (“Zhao”); in view of Kjellman et al. (WO 2016/128559 A1 – cited in IDS) (“Kjellman”); and Delgado et al. (Hematologia, 2002, 87, 215-216) (“Delgado”); as applied to claims 1-2, 4, 21-23, 26, and 32-34; further in view of Mei et al. (J. Hematol. Oncol., 2020, 13:161, 3 pages) (“Mei”).
The teachings of Zhao, Kjellman, and Delgado are disclosed above and incorporated herein.
While Zhao in view of Kjellman and Delgado do not teach treatment of thrombotic thrombocytopenia (TT) induced by a respiratory virus infection; the teachings of Mei are relied upon for these disclosures.
Mei teaches the incidence of thrombocytopenia on admission in COVID-19 was 36.2%, which is similar to that in SARS (40–45%%) and MERS (36%). Mai discloses it has been widely accepted that thrombocytopenia is indicative of disease severity, and a progressive decline of platelet counts was significantly associated with increased mortality (page 1, col. 2). Mei concludes that thrombocytopenia and thrombotic complications in COVID-19 patients are common and contribute to a higher mortality rate.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer (Zhao, Kjellman, and Delgado)’s rituximab-IdeS conjugate for the treatment of TT in a subject suffering from COVID19 induced TT. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because (Zhao, Kjellman, and Delgado) disclose their antibody-enzyme conjugate capable of treating immune conditions mediated by IgG or autoantibodies, including ITT and ATT; further because Mei teaches TT complications in COVID-19 patients are common and contribute to a higher mortality rate. Applicant is reminded, a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO 2020/257998 A1 – Int. Filing Date: 06/24/2019) (“Zhao”); in view of Kjellman et al. (WO 2016/128559 A1 – cited in IDS) (“Kjellman”); and Delgado et al. (Hematologia, 2002, 87, 215-216) (“Delgado”); as applied to claims 1-2, 4, 21-23, 26, and 32-34; further in view of Park et al. (Clinical and Experimental Pediatrics 2021; 64(8): 400-405 – Published Online June 30th, 2021) (“Park”).
The teachings of Zhao, Kjellman, and Delgado are disclosed above and incorporated herein.
While Zhao in view of Kjellman and Delgado do not teach treatment of vaccine-induced thrombotic thrombocytopenia (VITT); the teachings of Park are relied upon for these disclosures.
Park teaches thrombotic events after COVID19 vaccination are accompanied by thrombocytopenia, and this issue was recently termed vaccine-induced immune thrombotic thrombocytopenia (VIITT) (abstract). Park teaches VIITT occurring within 4-28 days after administration of COVID19 vaccine require attention (key message).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer (Zhao, Kjellman, and Delgado)’s rituximab-IdeS conjugate for the treatment of VITT, as disclosed by Park. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because (Zhao, Kjellman, and Delgado) disclose their antibody-enzyme conjugate capable of treating immune conditions mediated by IgG or autoantibodies, including ITT and ATT; further because Park teaches COVID19 vaccination resulted in VIITT. Therefore, one of ordinary skill would have been motivated to treat VIITT with (Zhao, Kjellman, and Delgado)’s rituximab-IdeS conjugate in view of Park. Applicant is reminded, a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
Prosecution Insights