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 .
Election/Restrictions
Applicant's election with traverse of the species (A) 14 days for duration of initiation cycle, (B) one dose increase during initiation cycle, (C) dose range of 18-240 mg during initiation cycle, (D) 14 days for duration of maintenance cycle, (E) twice every 7 days for dose interval of maintenance cycle, and (F) dose range of 72-360 mg during maintenance cycle in the reply filed on January 23, 2026 is acknowledged. The traversal is on the grounds that WO 2017182427 (“Zugmaier”) does not teach a bispecific antibody comprising an Fc domain (remarks, pg 8-9). This is not found persuasive because, in some embodiments, the bispecific construct of Zugmaier is based on the structure and/or function of an antibody [0023], “e.g. of a full-length or whole immunoglobulin molecule” [0024]. Therefore, Zugmaier teaches a bispecific antibody that is a full-length immunoglobulin comprised of a Fc domain. Also, Zugmaier teaches strategies for extending the half-life of antibody constructs, including fusion of the bispecific construct to the IgG Fc region [0134]. The requirement is still deemed proper and is therefore made FINAL.
Claims 10, 13-16, 22-24, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on January 23, 2026.
Claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, 44-45, 47-48, 50-53, and 108-109 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of PCT/US20/58720, which claims benefit to U.S. Provisional Application No. 62/930,433, filed November 4, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 3, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, 44-45, 47-48, and 50-53 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 1 is limited to an initiation cycle comprising administering “one or more doses of about 18 mg to about 480 mg once per day for 14 days”. This limitation is indefinite because it is unclear how much of the bispecific antibody is to be administered each day. In the case where more than one dose is administered at a time, the amount of antibody received by the patient could be unlimited. Claim 9 also uses similar indefinite phraseology.
The term “about” in claims 1, 9, 21, 27, and 33 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 1, 11-12, 25, 31, 39-40, 44-45, 47-48, and 50-53 are included in this rejection for being dependent on a rejected base claim and for failing to cure the indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, and 108 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.
“[T]he 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 specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, and 108 are directed to a method for treating myeloid leukemia by administering a bispecific antibody comprising first domain that binds CD33 and a second domain that binds to CD3. The bispecific antibody that binds CD33 and CD3 is only defined by its function, and thus the claims are directed to two broad genera of antigen binding domains that recognize CD33 and CD3.
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; PTO-892).
There is no way to a priori look at an antigen sequence (e.g., CD33 or CD3) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody that binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains.
According to the specification, the applicant has disclosed 9 anti-CD33 binding domains and 10 anti-CD3 binding domains (Specification, pg 69-70, Table 4), which are known in the art and are comprised of specific combinations of heavy chain and light chain sequences. However, the specification does not provide adequate written description for the entire claimed genus of anti-CD33/CD3 bispecific antibodies, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genus claimed, specifically which heavy chain and light chain amino acid sequences should be combined to yield an antigen-binding region that is capable of binding CD33 and CD3 and treating myeloid leukemia.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genera of anti-CD33 and anti-CD3 antigen-binding domains encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (instant PTO-892), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genera of antibodies that bind CD33 and CD3. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies and other agents that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible biantibodies and fails to provide a representative number of species for the claimed genera of antigen binding domains that recognize CD33 and CD3. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only 1 species within each genus.
For claims drawn to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). An antibody described only by functional characteristic, such as antibody that binds CD33, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, and 108 do not meet the written description requirement.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9, 11-12, 21, 25, 27, 31, 39, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017182427, published December 26, 2017 (“Zugmaier”; IDS from 5/3/2022).
The claims are directed to a method of treating myeloid leukemia comprising administering an anti-CD33/CD3 bispecific antibody construct with an Fc domain comprised of two Fc monomers. The method is comprised of an initiation cycle and a maintenance cycle.
Zugmaier teaches a bispecific construct comprising a first binding domain that recognizes CD33 and a second binding domain that binds to CD3 (a bispecific T cell engager or BiTE) for use in a method of treating myeloid leukemia (abstract; pg 1, ln 8-15), as in instant claim 1 . The myeloid leukemia is an acute myeloid leukemia (pg 42, ln 14), as in instant claim 39.
For the methods of claims 1, 9, 11-12, and 21, Zugmaier teaches that the bispecific construct is administered at a first dose followed by a second dose, where the second dose exceeds the first dose (pg 32, ln 25-31); the first period of administration is up to 7 days (pg 32, ln 33-34), and the period of the dose steps subsequent to the first period is 8-13 days (pg 33, ln 29-31). The dose range of the first phase may be 1-50 mg/day (pg 33, ln 9-12), as in the doses of instant claims 1, 9, 21, and 108. Preferred ranges for the second dose are 10 mg/day to 10 mg/day, more preferably 25 mg/day to 1 mg/day (pg 33, ln 20-25), as in instant claims 1, 21, 27, and 108. Stepwise dose increase is preferred in order to decrease immunologic side effects, e.g., cytokine release syndrome (pg 34, ln 1-5), as in the dose increase of instant claims 11-12 and 25. The duration of the cycles may comprise the maximal period of 14 days (pg 33, ln 29-33), as in instant claim 31.
Zugmaier teaches a half-life extended bispecific antibody construct comprising fusion of the bispecific construct to the IgG Fc region (pg 36, ln 19-24), as in the bispecific antibody construct comprising Fc of instant claim 1. Zugmaier teaches that respective equimolar doses for the bispecific antibody fused to Fc can be easily determined based on doses for the bispecific construct (pg 33, ln 13-18). Moreover, Zugmaier teaches for a half-life extended bispecific single chain antibody construct that the end of the administration phase must be planned in order to ensure a tapering below the threshold in line with the treatment schemata of the invention (pg 5, ln 15-21).
Zugmaier does not explicitly disclose the specific doses and dose intervals of the claims for the anti-CD33 x anti-CD3 bispecific antibody fused to two Fc monomers. However, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the teachings of Zugmaier, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the application was filed. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the dose of the anti-CD33 x anti-CD3 bispecific antibody of Zugmaier, because Zugmaier recognizes both dose and dose duration as result-effective variables and suggests the dose range 10 mg to 10 mg/day [0121] and the duration 4-10 days [0123]. Although the prior art does not explicitly teach the dosage regimen as claimed, it would be conventional and within the skill of the art to identify the optimal dosages administered. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method administer the same antibody construct to achieve the same results.
Claims 1, 9, 11-12, 21, 25, 27, 31, 39-40, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190127465 (“Zugmaier”), as applied to claims 1, 9, 11-12, 21, 25, 27, 31, 39, and 108 above, and further in view of Guy et al, published October 2, 2018 (instant PTO-892).
The teachings of Zugmaier are discussed above; Zugmaier does not explicitly disclose a method of treating relapsed/refractory acute myeloid leukemia.
Guy teaches a trial where the anti-CD33 x anti-CD3 BiTE AMG330 is administered to patients with relapsed/refractory acute myeloid leukemia (pg 420, column 1, para 1). Further, Guy teaches a related anti-CD33 x anti-CD3 BiTE construct, AMG673, which is the antibody construct AMG330 fused to an Fc domain to extend the half-life of the antibody (pg 420, column 1, para 1).
Given that Zugmaier teaches methods for the treatment of acute myeloid leukemia by administering an anti-CD33 x anti-CD3 bispecific antibody and further given that Guy teaches a trial for treating relapsed/refractory acute myeloid leukemia with the same antibody construct, it would have it would have been obvious to one of ordinary skill in the art to apply the therapeutic of Zugmaier for the treatment of refractory/relapsed acute myeloid leukemia. One would do so with a reasonable expectation of success, as Guy has expressly contemplated the use of this antibody in the treatment of subspecies of the disease that are not completely responsive to first-line therapy.
Claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39, 44-45, 47-48, 50-53, and 108-109 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190127465 (“Zugmaier”), as applied to claims 1, 9, 11-12, 21, 25, 27, 31, 39, and 108 above, and further in view of US 20170218078, published August 3, 2017 (“Raum”; instant PTO-892).
Regarding the bispecific antibody construct of claim 44, Zugmaier teaches the bispecific single chain antibody construct AMG 330, which consists of SEQ ID NO: 104 (pg 5, ln 13-14). AMG 330/SEQ ID NO: 104 is comprised of a first domain that binds to CD33 comprised of CDRH1-3 of instant SEQ ID NOs: 10, 13, and 14 and CDRL1-3 of instant SEQ ID NOs: 6, 8, and 9 and a second domain that binds to CD3 comprised of CHRH1-3 of instant SEQ ID NOs: 38, 44, and 49 and LCDR1-3 of instant SEQ ID NOs: 32, 33, and 36.
Zugmaier does not explicitly teach a construct comprising a third domain comprising two FC monomers comprising immunoglobulin hinge region, a CH2 domain, and a CH3 domain, where the monomers are fused to each other via a peptide linker of claim 44, nor does it explicitly disclose the specific sequences of instant claims 45, 48, 50-51, and 53.
Raum teaches an anti-CD33 x anti-CD3 bispecific antibody construct (half-life extended BiTE) comprised of SEQ ID NO: 180 [0213], which is identical to instant SEQ ID NO: 125 of instant claim 53. With respect to claim 44, this construct is comprised of two antigen binding domains and an Fc domain, where the first antigen binding domain is instant SEQ ID NO: 91 (as in claim 48), the second binding domain is instant SEQ ID NO: 91 (as in claim 48), the Fc monomers are instant SEQ ID NO: 19 (as in claim 50), and the third domain is instant SEQ ID NO: 117 (as in claim 51). This antibody construct is a single chain polypeptide, as in instant claim 52.
Regarding the limitation of intravenous infusion time of 30-90 min of instant claim 33, Raum teaches that the half-life extended BiTE formulation may be administered intravenously as a 30 min infusion [0451].
Given that Zugmaier teaches methods for the treatment of acute myeloid leukemia by administering an anti-CD33 x anti-CD3 bispecific antibody fused to the Fc region and further given that Raum teaches a half-life extended anti-CD33 x anti-CD3 BiTE, it would have been obvious to one of ordinary skill in the art to substitute the antibody construct of Raum in the method of Zugmaier and have a reasonable expectation of success. The motivation to do so comes from Raum, which teaches that continuous intravenous infusion of BiTE antibody constructs is classified as inconvenient for the patients, and antibody constructs with extended-half life are needed for less frequent dosing and patient convenience ([0002], [0294]). Further, as is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose (here the bispecific construct of Raum for the bispecific construct of Zugmaier) renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.”
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.
Claims 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, 44-45, 47-48, 50-53, and 108-109 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,933,132 in view of WO 2017182427, published December 26, 2017 (“Zugmaier”), Guy et al, published October 2, 2018, and US 20170218078, published August 3, 2017 (“Raum”). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: the same bispecific antibody construct that binds to CD33 and CD3 and a method of treating myeloid leukemia.
Claim 2 of ‘132 teaches a bispecific antibody construct comprised of a first domain of HCDR1-3 of SEQ ID NOs: 110-112 and LCDR1-3 of SEQ ID NOs: 115-117 and a second domain of HCDR1-3 of SEQ ID NOs: 231-232 and LCDR1-3 of SEQ ID NOs: 264-265, which read on the instant bispecific antibody construct of a first domain of HCDR1-3 of SEQ ID NOs: 10, 13, and 14 and LCDR1-3 of SEQ ID NOs: 6, 8, and 9 and a second domain of HCDR1-3 of SEQ ID NOs: 38, 44, and 49 and LCDR1-3 of SEQ ID NOs: 32, 33, and 36, respectively, of instant claims 44-45, 47-48, 50-53, and 109. Claim 7 of ‘132 teaches a method of treating a CD33 myeloid leukemia comprised of administering a pharmaceutical composition comprising the CD33 targeting compound, as in instant claim 1.
While the claims of ‘132 do not recite the doses and dosing duration of the instant claims or include a bispecific construct comprising an Fc domain, the claimed methods would have been obvious to one of ordinary skill in the art based on the additional teachings of Zugmaier, Guy, and Raum.
Zugmaier teaches a bispecific construct comprising a first binding domain that recognizes CD33 and a second binding domain that binds to CD3 (a bispecific T cell engager or BiTE) for use in a method of treating myeloid leukemia (abstract; pg 1, ln 8-15), as in instant claim 1 . The leukemia is an acute myeloid leukemia (pg 42, ln 14), as in instant claim 39.
For the methods of claims 1, 9, 11-12, 21, Zugmaier teaches that the bispecific construct is administered at a first dose followed by a second dose, where the second dose exceeds the first dose (pg 32, ln 25-31). The first period of administration if up to 7 days (pg 32, ln 33-34), and the period of the dose steps subsequent to the first period is 8-13 days (pg 33, ln 29-31). The dose range of the first phase may be 1-50 mg/day (pg 33, ln 9-12), as in the doses of instant claims 1, 9, 21, and 108. Preferred ranges for the second dose are 10 mg/day to 10 mg/day, more preferably 25 mg/day to 1 mg/day (pg 33, ln 20-25), as in instant claims 1, 21, 27, and 108. Stepwise dose increase is preferred in order to decrease immunologic side effects, e.g., cytokine release syndrome (pg 34, ln 1-5), as in the dose increase of instant claims 11-12 and 25. The duration of the cycles may comprise the maximal period of 14 days (pg 33, ln 29-33), as in instant claim 31.
Zugmaier teaches a half-life extended bispecific antibody construct comprising fusion of the bispecific construct to the IgG Fc region (pg 36, ln 19-24), as in the bispecific antibody construct comprising Fc of instant claim 1. Zugmaier teaches that respective equimolar doses for the bispecific antibody fused to Fc can be easily determined based on doses for the bispecific construct (pg 33, ln 13-18). Moreover, Zugmaier teaches for a half-life extended bispecific single chain antibody construct that the end of the administration phase must be planned in order to ensure a tapering below the threshold in line with the treatment schemata of the invention (pg 5, ln 15-21).
‘132 in view of Zugmaier does not explicitly disclose the specific doses and dose intervals of the claims for the anti-CD33 x anti-CD3 bispecific antibody fused to two Fc monomers. However, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the teachings of Zugmaier, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was filed. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the dose of the anti-CD33 x anti-CD3 bispecific antibody of Zugmaier, because Zugmaier recognizes both dose and dose duration as result-effective variables and suggests the dose range 10 mg to 10 mg/day [0121] and the duration 4-10 days [0123]. Although the prior art does not explicitly teach the dosage regimen as claimed, it would be conventional and within the skill of the art to identify the optimal dosages administered. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method administer the same antibody construct to achieve the same results.
The teachings of ‘132 in view of Zugmaier are discussed above; ‘132 in view of Zugmaier does not explicitly disclose a method of treating relapsed/refractory acute myeloid leukemia.
Guy teaches a trial where the anti-CD33 x anti-CD3 BiTE AMG330 is aministered to patients with relapsed/refractory acute myeloid leukemia (pg 420, column 1, para 1). Further, Guy teaches a related anti-CD33 x anti-CD3 BiTE construct, AMG673, which is the antibody construct AMG330 fused to an Fc domain to extend the half-life of the antibody (pg 420, column 1, para 1).
Given that Zugmaier teaches methods for the treatment of acute myeloid leukemia by administering an anti-CD33 x anti-CD3 bispecific antibody and further given that Guy teaches a trial for treating relapsed/refractory acute myeloid leukemia with the same antibody construct, it would have it would have been obvious to one of ordinary skill in the art to apply the therapeutic of ‘132 in view of Zugmaier for the treatment of refractory/relapsed acute myeloid leukemia. One would do so with a reasonable expectation of success, as Guy has expressly contemplated the use of this antibody in the treatment of subspecies of the disease that are not completely responsive to first-line therapy.
‘132 in view of Zugmaier does not explicitly teach a construct comprising a third domain comprising two FC monomers comprising immunoglobulin hinge region, a CH2 domain, and a CH3 domain, where the monomers are fused to each other via a peptide linker, nor does it explicitly disclose the specific sequences of instant claims 45, 48, 50-51, and 53.
Raum teaches an anti-CD33 x anti-CD3 bispecific antibody construct (half-life extended BiTE) comprised of SEQ ID NO: 180 [0213], which is identical to instant SEQ ID NO: 125 of instant claim 53. With respect to claim 44, this construct is comprised of two antigen binding domains and an Fc domain, where the first antigen binding domain is instant SEQ ID NO: 91 (as in claim 48), the second binding domain is instant SEQ ID NO: 91 (as in claim 48), the Fc monomers are instant SEQ ID NO: 19 (as in claim 50), and the third domain is instant SEQ ID NO: 117 (as in claim 51). This antibody construct is a single chain polypeptide, as in instant claim 52.
Regarding the limitation of intravenous infusion time of 30-90 min of instant claim 33, Raum teaches that the half-life extended BiTE formulation may be administered intravenously as a 30 min infusion [0451].
Given that ‘132 in view of Zugmaier teaches methods for the treatment of acute myeloid leukemia by administering an anti-CD33 x anti-CD3 bispecific antibody fused to the Fc region and further given that Raum teaches a half-life extended anti-CD33 x anti-CD3 BiTE, it would have been obvious to one of ordinary skill in the art to substitute the antibody construct of Raum in the method of ‘132 in view of Zugmaier and have a reasonable expectation of success. The motivation to do so comes from Raum, which teaches that continuous intravenous infusion of BiTE antibody constructs is classified as inconvenient for the patients and antibody constructs with extended-half life are needed for less frequent dosing and patient convenience ([0002], [0294]). Further, as is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose (here the bispecific construct of Raum for the bispecific construct of ‘132 in view of Zugmaier) renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.”
The scope of the instant claims are fully encompassed in the reference claims in view of Zugmaier, Guy, and Rau, and it would have been obvious to one of ordinary skill in the art that the method and antibody of ‘132 are the same as those of the instant claims. Therefore, the claims of the instant application and patent ‘132 are not patentably distinct from each other.
Claim 1, 9, 11-12, 21, 25, 27, 31, 33, 39-40, 44-45, 47-48, 50-53, and 108-109 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-28 of copending Application No. 17/927,071 in view of in view of WO 2017182427, published December 26, 2017 (“Zugmaier”) and US 20170218078, published August 3, 2017 (“Raum”). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method for treating relapsed/refractory myeloid leukemia comprised of administering a bispecific construct that binds CD33 and CD3, wherein the treatment cycles are comprised of increasing dose steps, as in instant claims 1 and 39-40. The doses and dosing intervals of ‘071 claims 15-21 overlaps with those of instant claims 1, 9, 11-12, 21, 25, 27, 31, and 33.
Claims 24 and 25 of ‘071 teaches a bispecific antibody construct comprised of a first domain of HCDR1-3 of SEQ ID NOs: 94-96 and LCDR1-3 of SEQ ID NOs: 98-100 and a second domain of HCDR1-3 of SEQ ID NOs: 202-204 and LCDR1-3 of SEQ ID NOs: 205-207, which read on the bispecific antibody construct of a first domain of HCDR1-3 of SEQ ID NOs: 10, 13, and 14 and LCDR1-3 of SEQ ID NOs: 6, 8, and 9 and a second domain of HCDR1-3 of SEQ ID NOs: 38, 44, and 49 and LCDR1-3 of SEQ ID NOs: 32, 33, and 36, respectively, of claims 44-45, 47-48, 50-53, and 109.
‘071 does not explicitly disclose the specific doses and dose intervals of the claims for the anti-CD33 x anti-CD3 bispecific antibody fused to two Fc monomers.
Zugmaier teaches a half-life extended bispecific antibody construct comprising fusion of the bispecific construct to the IgG Fc region (pg 36, ln 19-24), as in the bispecific antibody construct comprising Fc of instant claim 1. Zugmaier teaches that respective equimolar doses for the bispecific antibody fused to Fc can be easily determined based on doses for the bispecific construct (pg 33, ln 13-18). Moreover, Zugmaier teaches for a half-life extended bispecific single chain antibody construct that the end of the administration phase must be planned in order to ensure a tapering below the threshold in line with the treatment schemata of the invention (pg 5, ln 15-21).
‘071 in view of Zugmaier does not explicitly disclose the specific doses and dose intervals of the claims for the anti-CD33 x anti-CD3 bispecific antibody fused to two Fc monomers. However, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the teachings of ‘071 and Zugmaier, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was filed. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the dose of the anti-CD33 x anti-CD3 bispecific antibody of ‘071, because ‘071 recognizes both dose and dose duration as result-effective variables and suggests the dose 10 mg/day [0121] and the duration of 15 days [0123]. Although the prior art does not explicitly teach the dosage regimen as claimed, it would be conventional and within the skill of the art to identify the optimal dosages administered. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
‘071 in view of Zugmaier does not teach a construct comprising a third domain comprising two FC monomers comprising immunoglobulin hinge region, a CH2 domain, and a CH3 domain, where the monomers are fused to each other via a peptide linker, nor does it explicitly disclose the specific sequences of instant claims 45, 48, 50-51, and 53.
Raum teaches an anti-CD33 x anti-CD3 bispecific antibody construct (half-life extended BiTE) comprised of SEQ ID NO: 180 [0213], which is identical to instant SEQ ID NO: 125 of instant claim 53. With respect to claim 44, this construct is comprised of two antigen binding domains and an Fc domain, where the first antigen binding domain is instant SEQ ID NO: 91 (as in claim 48), the second binding domain is instant SEQ ID NO: 91 (as in claim 48), the Fc monomers are instant SEQ ID NO: 19 (as in claim 50), and the third domain is instant SEQ ID NO: 117 (as in claim 51). This antibody construct is a single chain polypeptide, as in instant claim 52.
Regarding the limitation of intravenous infusion time of 30-90 min of instant claim 33, Raum teaches that the half-life extended BiTE formulation may be administered intravenously as a 30 min infusion [0451].
Given that ‘071 in view of Zugmaier teaches methods for the treatment of acute myeloid leukemia by administering an anti-CD33 x anti-CD3 bispecific antibody fused to the Fc region and further given that Raum teaches a half-life extended anti-CD33 x anti-CD3 BiTE, it would have been obvious to one of ordinary skill in the art to substitute the antibody construct of Raum in the method of ‘071 in view of Zugmaier and have a reasonable expectation of success. The motivation to do so comes from Raum, which teaches that continuous intravenous infusion of BiTE antibody constructs is classified as inconvenient for the patients and antibody constructs with extended-half life are needed for less frequent dosing and patient convenience ([0002], [0294]). Further, as is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose (here the bispecific construct of Raum for the bispecific construct of ‘071 in view of Zugmaier) renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.”
The scope of the instant claims are fully encompassed in the reference claims in view of Zugmaier and Rau, and it would have been obvious to one of ordinary skill in the art that the method and antibody of ‘071 are the same as those of the instant claims. Therefore, the claims of the two applications are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675