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 of Group I drawn to a composition comprising a multispecific protein, a buffer, an excipient, and a surfactant; and species comprising a discrete pair of first and second binding domains, wherein the first binding domain comprises CD123 at the N-terminus and the second binding domain comprises CD3 at the C-terminus in the reply filed on 6/9/2026 is acknowledged. Because applicant did not distinctly and specifically point out whether the election is with or without traverse in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-2, 4-6, 8-10, 13-14, 16-19, 21, 26-27, 29, 31, 34-36, 38-40, 42-49, 53-54, 57-59, 61-62, 67-69, 72, 74-77, 80-82, 84-87, 89-91, 93-101, 106-113, 114-117, 119, 124-126, 130-132, 137, 144, and 147-157 are pending in the instant application.
Claims 1-2, 4-6, 8-10, 13-14, 16-19, 21, 26, 34-36, 38-40, 42-49, 53-54, 57-59, 61-62, 67-69, 72, 74-77, 80-82, 84-87, 89-91, 93-101, and 106-113 are being examined on the merits.
Claims 114-117, 119, 124-126, 130-132, 137, 144, and 147-157 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/9/2026.
Claims 27, 29, and 31 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/9/2026.
Information Disclosure Statement
The information disclosure statement filed 5/1/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following documents listed below:
Reference No. 063 (ISIDORI et al, 2012)
The information disclosure statement filed 5/1/2024 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following documents listed below:
Marvin and Zhu, Acta Pharmacologica Sinica, 2005.
Specification
The disclosure is objected to because of the following informalities:
“D.A.R.T.s” should read “DARTs” (page 3, ¶ [0009]; page 29, ¶ [0001]);
The paragraph numbering “[0001]” should be “[0090]”, and ¶ [0090]-[0258] on pages 29-97 following “¶ [0001]” should be corrected accordingly; and
“DNLs@” should read “DNLs®” (page 2, ¶ [0009]).
Appropriate correction is required.
The use of the term BiTE®, Nanobody®, CrossMab®, Affibody®, Fynomer®, Albu-dAbTM, DART®, DVD-IGTM, DuoBody®, and Triomab®, 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.
Examples of pages requiring such corrections in the instant specification include, but are not limited to, the following:
BiTE® (page 3, ¶ [0009]; page 29, ¶ [0001]);
Nanobody® (page 2, ¶ [0009]; page 29, ¶ [0001]);
CrossMab® (page 2, ¶ [0009]; page 29, ¶ [0001]);
Affibody® (page 3, ¶ [0009]; page 29, ¶ [0001]);
Fynomer® (page 3, ¶ [0009]; page 29, ¶ [0001]);
Albu-dAbTM (page 3, ¶ [0009]; page 29, ¶ [0001]);
DART® (page 3, ¶ [0009]; page 29, ¶ [0001]);
DVD-IGTM (page 3, ¶ [0009]; page 29, ¶ [0001]);
DuoBody® (page 3, ¶ [0009]; page 29, ¶ [0001]); and
Triomab® (page 3, ¶ [0009]; page 29, ¶ [0001]).
Claim Objections
Claim 107 is objected to because of the following informalities:
“D.A.R.T.” should read DART in claim 107.
Appropriate correction is required.
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.
Claim 107 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 107 recites exemplary language that renders the claim indefinite because it is unclear whether the limitation is part of the claimed invention. In regards to the phrase scFv x scFv (BiTE)”, it is unclear if the term enclosed in the parentheses is intended to be exemplary, because the phrase “scFv x scFv” broadly defines a structural genus of any two single-chain variable fragments connected by a linker whereas a “BiTE” (Bispecific T-cell Engager) is a distinct, functionally limited species of an scFv x scFv wherein one scFv specifically binds to a protein on T cells and the second scFv binds to a target antigen. Therefore, it is unclear whether the limitation in the parentheses is part of the claimed invention.
Furthermore, claim 107 also recite exemplary language in the parentheses following the phrase “IgG1 antibodies comprising matched mutations in the CH3 domain (e.g. DuoBody® antibody)”, wherein the limitation in the parentheses renders the claim indefinite, because the metes and bounds of the claim is unclear whether the limitation in the parentheses following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 107 contains the trademark/trade name(s) BiTE®, SMIPTM, Nanobody®, DOCK-AND-LOCK®, DNL®, CrossMab®, Affibody®, Fynomer®, Albu-dAbTM, DART®, DVD-IGTM, DuoBody®, and Triomab®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the fusion protein of the composition and, accordingly, the identification/description is indefinite.
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 43-44, 46-48, 94-95, and 97-99 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 claims contain 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. The courts have stated: "To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966." Regents" of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents" of the University of California v. Eli Lilly & Co. the court stated: "A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171,25 USPQ2d 1601 ; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163 does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. A "representative number of species" means that the species, which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Furthermore, possession of a genus may not be shown by merely describing how to obtain members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). The courts have held that possession of a genus may not be shown by merely describing how to obtain members of the claimed genus (i.e. make and test to see if they lack the requisite activity) or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895 and In re Kubin, 90 USPQ2d 1417 (Fed. Cir. 2009). In addition, the court has held that a method of identification of compounds (i.e. screening for variants) is not a description of the compounds per se that meet the requisite function to use in the associated methods. University of Rochester v. G.D. Searle & Co. 69 USPQ2D 1886 (CAFC 2004. Finally, function does not describe a structure, because the specification does not provide relevant identifying characteristics, including functional characteristics when coupled with known or disclosed correlation between function and structure. The courts have held that in these instances, the specification lacks written description see Enzo Biochem Inc. v. Gen-Probe Inc. 63 USPQ2D 1609 (CAFC 2002) and University of Rochester v. G.D. Searle & Co. 69 USPQ2D 1886 (CAFC 2004).
Claimed Invention
Instant claims 43-44, 46-48, 94-95, and 97-99, are drawn to a composition comprising a multispecific protein, wherein the multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino-terminus to carboxyl terminus, or in order from carboxyl-terminus to amino-terminus (i) a first binding domain that binds to a tumor antigen; (ii) a hinge region; (iii) an immunoglobulin constant region; and (iv) a second binding domain that binds to CD3.
Instant claims 43 and 94 recite an anti-CD123 scFv comprising a VH comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:136 and a VL comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:134.
Instant claims 44 and 95 recite an anti-CD123 scFv comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:18.
Instant claims 46 and 97 recite an anti-CD3 scFv comprising a VH comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:383 or 387 and a VL comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:384.
Instant claims 47 and 98 recite an anti-CD3 scFv comprising a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:27.
Instant claims 48 and 99 recite the polypeptide comprising the composition, wherein the polypeptide comprises a sequence at least 90%, at least 95%, or 100% identical to SEQ ID NO:31.
Breadth of Claims
The invention as disclosed in claims 43-44, 46-48, 94-95, and 97-99 recite a composition comprising a multispecific protein, wherein the multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino-terminus to carboxyl terminus, or in order from carboxyl-terminus to amino-terminus (i) a first binding domain that binds to a tumor antigen; (ii) a hinge region; (iii) an immunoglobulin constant region; and (iv) a second binding domain that binds to CD3. The claims encompass a genus of heavy and light chain variable regions comprising variability (e.g., 90% or 95% identical) in both the heavy and light chain variable regions which are claimed as having the function of specifically binding to CD123 or CD3 antigen. This means that the variability in sequence identity (e.g., 90% or 95% sequence identify) 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 CD123 or CD3 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 still result in performing the requisite functions of the specific binding of CD123 or CD3 antigen.
Summary of Disclosed Species in the Original Specification
The composition comprising the anti-CD123 and CD3 multispecific protein in the Applicant disclosure (e.g. see §Examples on pages 87-97) represent anti-CD123 and anti-CD3 multispecific protein compositions that the Applicant was in possession of at the time of filing. The instant disclosure of the elected species of the multispecific protein comprising a discrete pair of first and second binding domains, wherein the first binding domain comprises CD123 at the N-terminus and the second binding domain comprises CD3 at the C-terminus, are particular scFvs having a particular inherent combination of heavy and light chain CDRs (see instant claims 42 and 93 for CD123, and instant claims 45 and 96 for CD3) that define its ability to bind CD123 or CD3 (e.g. see Table 4-5).
However, the specification does not describe the random combination of heavy and light chain variable regions or CDR's fragments therefrom to prepare a multispecific protein that binds to CD123 and CD3. The specification does not disclose a representative number of multispecific proteins with the claimed binding characteristics. The disclosed binding proteins (e.g. TRI129 and TRI130) have a specific CDR structure that binds a particular CD123 and CD3. The specification does not, however, disclose a correlation of structure with the function by means of a representative number of CD123 or CD3 binding domains that have the requisite claimed functional properties. Therefore, the specification does not provide for a structure-function correlation of binding proteins representative of the full scope of the genus. Furthermore, it is clear that the specification does not describe binding proteins with particular functional properties or combinations of different CDRs. The specification does not describe a correlation of the structure of the CD123- or CD3-binding domains with the functional properties as claimed (e.g. percent identical variants) absent the presence of the specifically disclosed CDRs in specific order that convey the structure that correlates with the binding function as claimed. Variations to the CDRs and to any framework regions that affect binding do not have description for the broad scope of the claims.
State of the Prior Art
It is well established that changes in the amino acid sequence of the variable region of an antibody create new antibodies with highly unpredictable binding characteristics. See for example Chen et al (Chen et al, “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations”, 1995, The EMBO Journal, 14(12):2784-2794). Chen teaches that the substitution of a single amino acid can totally ablate antigen binding (Figure 1), however, the reference additionally teaches that the same substitution in closely related antibodies can have opposite effects. The authors compared the effects of identical substitution in related antibodies D16 and T15, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. Additionally, Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983) teach that such is necessary and conventional to define an antibody that specifically binds a cognate antigen.
At the time of filing, antibody functionality was 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 mutation to CDRs is unpredictable and that each construct requires function testing (Sela-Culang et al, “The structural basis of antibody-antigen recognition”, 2013, Fron. Immuno., 4(302): 1-13; hereinafter Sela-Culang). 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 (page 1, Abstract; page 3, “The Role of CDRs and their Definition” section). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (page 1, “The Motivations for, and Applications of, the Study of Ab-Ag Recognition” Section).
Further, Herold (Herold et al, “Determinants of the assembly and function of antibody variable domains”, 2017, Nature Scientific Reports, 7(12276):1-17; 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 (page 14, paragraph 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex ( page 14, paragraph 3). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983). Rudikoff et al teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
At the time of filing Albrecht et al (WO2018015340A1, priority to July 18, 2016) teaches antibody-like binding protein specifically to CD3 and CD123, wherein the CD3-binding arm (described as “hz20G6) and CD123-binding arm (described as “anti-CD123 mAb 7G3”) comprises HCDR1-3 and LCDR1-3 to bind CD3 and CD123 target antigens (page 1, Abstract; page 3, lines 33-36; page 6, lines 29-31). Furthermore, Albrecht teaches sequence variants wherein the CDRs will typically not be altered in connection with humanization, while the framework/constant region residues are allowed to vary within a given threshold (e.g. ≥85%) (page 12, lines 22-24; page 14, lines 7-21). Furthermore, Albrecht teaches that the single chain CD123 x CD3 bispecific diabody in DART format (hereinafter MDF006) caused significantly more T-cell activation in the absence of target cells (page 82-83, Example 1; Table 1) and lower KD for CD3 and CD123 compared to other variants (page 83, Table 3). For other variants, Albrecht discloses that the binding kinetics to CD3 and CD123 are similar (pages 93-94, §2.6; Table 7). Additionally, introduction of backbone mutations without altering the CDRs did not cause any loss of activity in T-cell engaging (page 96-97, §2.8; Table 9) and did not induce unwanted effects in regard to T-cell activation in the absence of target cells (page 98, Tables 10 and 11).
Kuo (Kuo et al, “Engineering a CD123xCD3 bispecific scFv immunofusion for the treatment of Leukemia and elimination of leukemia stem cells”, June 27 2012, Protein Engineering, Design and Selection, 25(10):561-570; hereinafter Kuo) teaches a bispecific single-chain Fv (scFv) immunofusion or BIf to target CD123+ leukemia, that contains an anti-CD123 scFv fused at the N-terminus of human IgG1 hinge-CH2-CH3, and an anti-CD3 scFv fused at the C-terminus (page 561, Abstract). Kuo discloses that when expressed from transfected CHO-S cells, CD123xCD3 BIf forms a homodimer that provides a structure of the N-terminal tumor-targeting domain that closely resembles the natural antibody (page 561, Abstract; page 562, left column, second paragraph). Kuo also teaches that the CD123xCD3 dimeric structure provides binding affinity to CD123+ tumor cells with a Kd of 10−10 M, one to two orders of magnitude stronger than traditional bispecific antibody constructs (page 564-565, §Cell surface CD123 binding activities; Fig. 2). Additionally, the location of the anti-CD3 scFv at the C-terminus of BIf reduces the binding affinity to CD3+ T cells by two orders, which helps to prevent non-specific T-cell activation (page 565, §T-cell binding activities; Fig. 3), and the CD123xCD3 BIf is able to achieve T-cell-mediated target cell killing activities at low pM levels with E/T ratios as low as 2 (page 565-566, §Bif -mediated T-cell cytotoxicities; Fig. 4-6). Furthermore, Kuo teaches the inclusion of human IgG1 constant region in the BIf construct increases target cell-binding affinity, potentially increases serum half-life by its larger size and FcRn-mediated salvage system, and includes the ability to activate the additional antibody-mediated cellular cytotoxicities (page 567, third paragraph – page 568, first paragraph).
The prior art, however, does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-CD123 and anti-CD3 multispecific binding protein that would allow prediction of CDR residues that specifically bind to CD123 and CD3 antigens. 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).
Conclusion
For all the foregoing reasons, in view of the substantial genus of variant multispecific binding proteins, the numerous factors impinging binding and function of the multispecific proteins to the target and also having the specifically claimed function, and the lack of description of a representative number of binding proteins that function as claimed, the composition comprising the multispecific binding protein is not described in the specification in such a way as to reasonably convey to one skilled in the art that the Applicant, at the time the application was filed, had possession of the claimed invention. 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 the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claims 43-44, 46-48, 94-95, and 97-99 would need to recite the 6 CDRs in the antibody that bind antigens CD123 and CD3 without variability in the sequences thereof.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4-6, 8-9, 13-14, 16-19, 21, 26, 34-36, 38-40, 49, 53-54, 57-59, 61-62, 67-68, 72, 74-77, 80-82, 84-87, 89-91, 101, and 107 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan).
Regarding claims 1-2, 4-6, 8-9, 13-14, 18-19, 21, 26, 61, 67-68, 72, and 84, Tan teaches a CD3-binding homodimeric protein comprising two identical, disulfide-bonded polypeptides (page 28, ¶ [0070], wherein the CD3-binding polypeptide comprises, in order from amino-terminus to carboxyl-terminus, (i) a second binding domain comprising a tumor antigen-binding domain, e.g. CD123 (page 26, ¶ [0053]; page 32, ¶ [0102]), (ii) a hinge region, (iii) an immunoglobulin constant region, a carboxyl-terminus or amino-terminus linker, and (v) a CD3 binding domain (page 23, ¶ [0020]). Tan also teaches the CD3-binding protein formulated as a pharmaceutical composition comprising the CD3-binding polypeptide and a pharmaceutically acceptable carrier (page 47, ¶ [0203]) administered to a subject in a therapeutically effective amount via intravenous administration (page 47, ¶ [0205]), wherein the CD3-binding protein is diluted into formulation buffer (which was used for all dilutions) comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 (pages 53-54, ¶ [0261]).
Regarding claims 16-17 and 74, Tan teaches the immunoglobulin constant region comprising a human IgG1 Fc domain, wherein the Fc domain comprises IgG1 CH2, and CH3 domains (pages 22-23, ¶ [0018]); page 28, ¶ [0067]-[0068]).
Regarding claims 34 and 85, Tan teaches that the CD3-binding polypeptide (e.g., multispecific), wherein (i) the CD3-binding domain comprises (a) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and (b) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3; and (ii) the second binding domain comprises (a) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and (b) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3. (page 23, ¶ [0020]).
Regarding claims 35-36, 38-39, 86-87, and 89-90, Tan discloses a CD3-binding domain that is a single chain variable fragment (scFv) comprising a linker between the heavy chain variable region and a light chain variable region, wherein the light chain variable region of the scFv is amino terminal to the heavy chain variable region of the scFv (page 22, ¶ [0012]).
Regarding claims 40 and 91, Tan teaches that the peptide linker joining the VL and VH regions comprises a 15mer consisting of three repeats of a Gly-Gly-Gly-Gly-Ser amino acid sequence ((Gly4Ser)3) (SEQ ID NO:193) (page 34-35, ¶ [0123]).
Regarding claims 49, 53, 76, and 101, Tan teaches that an altered CH2 region can comprise one or more (e.g., two, three, four or five) amino acid deletions in the human immunoglobulin CH2 region at positions 234-238, for instance, at one of position 236 or position 237 while the other position is substituted, wherein the mutation(s) decrease or eliminate the antibody-dependent cell-mediated cytotoxicity (ADCC) activity (page 40, ¶ [0154]).
Regarding claims 54 and 77, Tan discloses that an immunoglobulin constant region comprises a human IgG1 CH2 domain comprising the substitutions L234A, L235A, G237A, and K322A, according to the EU numbering system (pages 22-23, ¶ [0018]).
Regarding claims 57 and 80, Tan teaches that the hinge of the polypeptide is a wild-type human immunoglobulin hinge (page 27, ¶ [0063]; page 35, ¶ [0124]).
Regarding claims 58-59 and 81-82, Tan teaches a CD3-binding polypeptide comprising a carboxyl-terminus or amino-terminus linker between the immunoglobulin constant region and the CD3 binding domain, wherein the linker comprises about 15 to about 25 amino acids, e.g. flexible linkers comprising glycine-serine repeats (page 27, ¶ [0062]).
Regarding claims 62 and 101, Tan teaches that the humanized anti-CD3 binding proteins had improved properties (e.g., thermal stability, storage stability, serum half-life, reduced formation of high molecular weight aggregates) compared to other anti-CD3 binding domains and proteins, e.g. DRA222 (page 25, ¶ [0050]; page 53, ¶ [0260], Table 13).
Regarding claim 107, Tan teaches a CD3-binding protein formulated as a pharmaceutical composition diluted in formulation buffer as described above in claim 1 of the 102 rejection, wherein the protein may be an scFv-Fc-scFv molecule (page 30, ¶ [0086]).
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 42-48, 93-100, 106, 108-110 are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan), and further in view of Hernandez-Hoyos (Hernandez-Hoyos et al, WO2018057802A1, Priority to 9/21/2016, Published on 3/29/2018, IDS entered on 5/12/2023; hereinafter Hernandez-Hoyos).
Regarding instant claims 42-48, 93-100, 106, and 108-110, the teachings of Tan are discussed above in the 102 rejection.
However, Tan does not teach a composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO:31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the amino acid sequence instant SEQ ID NO:18 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:10-12, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:134 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:13-15, respectively;
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:19-21, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:384 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:22-24, respectively; and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
The deficiency is resolved by Hernandez-Hoyos.
Hernandez-Hoyos teaches pharmaceutical compositions comprising a CD123-binding polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the CD123-binding polypeptide comprises, in order from amino to carboxyl terminus, (i) a human or humanized CD123-binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl-terminus linker, and (v) a human or humanized second binding domain that specifically binds CD3 (pages 11-12, ¶ [0023]; pages 95-96, ¶ [00193]). Hernandez-Hoyos discloses that formulations can further include one or more excipients, preservatives, solubilizers, buffering agents, or albumin to prevent protein loss (pages 107-108, ¶ [00225]). Hernandez-Hoyos also teaches that the recombinant polypeptide comprising a CD123-binding domain comprises (i) an immunoglobulin light chain variable region comprising LCDR1 comprising the amino acid sequence SEQ ID NO:6 (identical to instant SEQ ID NO:13); the LCDR2 comprising the amino acid sequence SEQ ID NO:8 (identical to instant SEQ ID NO:14); the LCDR3 comprising the amino acid sequence SEQ ID NO:10 (identical to instant SEQ ID NO:15); and (ii) an immunoglobulin heavy chain variable region comprising HCDR1 comprising the amino acid sequence SEQ ID NO:12 (identical to instant SEQ ID NO:10); the HCDR2 comprising the amino acid sequence SEQ ID NO:14 (identical to instant SEQ ID NO:11); and the HCDR3 comprising the amino acid sequence SEQ ID NO:16 (identical to instant SEQ ID NO:12) (pages 4-5, ¶ [006]; Table 3). Additionally, Hernandez-Hoyos discloses that the CD123-binding polypeptide comprises the CD123 binding domain of amino acid sequence SEQ ID NO:132, wherein the CD123-binding domain comprises: (i) the immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:2; and (ii) the immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 (pages 4-5, ¶ [006]; pages 10-11, ¶ [0018]; Table 3). SEQ ID NOs:132, 2, and 4 are identical to instant SEQ ID NOs:18, 134, and 136, respectively. Hernandez-Hoyos also teaches a second binding domain that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 (identical to instant SEQ ID NO:27), wherein the CD3 binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence SEQ ID NO:157 and an immunoglobulin heavy chain variable region comprising the amino acid sequence SEQ ID NO:159, wherein the VL comprising the amino acid sequence SEQ ID NO:157 comprises LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences instant SEQ ID NOs:22-24, respectively; and the VH comprising the amino acid sequence SEQ ID NO:159 comprises HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences instant SEQ ID NOs:19, 20, and 21 (pages 46-47, ¶ [00139]; pages 95-96, ¶ [00193]; Table 3). Furthermore, Hernandez-Hoyos teaches that the polypeptide comprising CD123- and CD3-binding domains comprises the amino acid sequence SEQ ID NO:132, wherein the polypeptide also contains a secretory signal sequence comprising the amino acid sequence SEQ ID NO:198 (pages 10-11, ¶ [0018]; page 89, ¶ [00180]; page 100, ¶ [00205]). SEQ ID NO:132 with the secretory signal (SEQ ID NO:198) is identical to instant SEQ ID NO:31.
Regarding instant claims 42-48, 93-100, 106, and 108-110, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the composition comprising:
a multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain that specifically binds CD123,
A hinge region,
An immunoglobulin constant region, and
A second binding domain that specifically binds to CD3; and
5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8
as taught by the combined teachings of Tan and Hernandez-Hoyos to include that the
the polypeptide comprising the multispecific protein dimer comprises the amino acid sequence SEQ ID NO:132 with a secretory signal sequence comprising the amino acid sequence SEQ ID NO:198, wherein (i) the CD123-binding scFv comprises the CD123 binding domain of amino acid sequence SEQ ID NO:132, wherein the VH comprising HCDR1-3 comprises the amino acid sequence SEQ ID NO:4, and the VL comprising LCDR1-3 comprises the amino acid sequence SEQ ID NO:2; and (ii) the CD3-binding scFv comprises the amino acid sequence SEQ ID NO:312, which is the CD3 binding domain of amino acid sequence SEQ ID NO:132, wherein the VH comprising HCDR1-3 comprises the amino acid sequence SEQ ID NO:159, and the VL comprising LCDR1-3 comprises the amino acid sequence SEQ ID NO:157 as taught by Hernandez-Hoyos. This is obvious because, the combined teachings of Tan and Hernandez-Hoyos teach a composition comprising:
a multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain that specifically binds CD123,
A hinge region,
An immunoglobulin constant region, and
A second binding domain that specifically binds to CD3; and
a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
and Hernandez-Hoyos teaches a polypeptide comprising the amino acid sequence SEQ ID NO:132 with a secretory signal sequence comprising the amino acid sequence SEQ ID NO:198, wherein (i) the CD123-binding scFv comprises the CD123 binding domain of amino acid sequence SEQ ID NO:132, wherein the VH comprising HCDR1-3 comprises the amino acid sequence SEQ ID NO:4, and the VL comprising LCDR1-3 comprises the amino acid sequence SEQ ID NO:2; and (ii) the CD3-binding scFv comprises the amino acid sequence SEQ ID NO:312, which is the CD3 binding domain of amino acid sequence SEQ ID NO:132, wherein the VH comprising HCDR1-3 comprises the amino acid sequence SEQ ID NO:159, and the VL comprising LCDR1-3 comprises the amino acid sequence SEQ ID NO:157. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO:31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the amino acid sequence instant SEQ ID NO:18 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:10-12, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:134 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:13-15, respectively;
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:19-21, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:384 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:22-24, respectively; and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
Claims 10, 69, and 113 are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan) and Hernandez-Hoyos (Hernandez-Hoyos et al, WO2018057802A1, Priority to 9/21/2016, Published on 3/29/2018, IDS entered on 5/12/2023; hereinafter Hernandez-Hoyos) as applied to claims 1, 67, and 108 above, and further in view of Park (Park et al, WO2015200027A1, Priority to 6/26/2014; hereinafter Park).
Regarding instant claims 10, 69, and 113, the combined teachings of Tan and Hernandez-Hoyos are discussed above.
However, the combined teachings of Tan and Hernandez-Hoyos do not teach the composition comprising a multispecific protein and a formulation buffer wherein the composition comprises about 0.1 mg/ml to about 10mg/ml of the multispecific protein.
The deficiency is resolved by Park.
Park teaches methods of making solid and liquid protein formulations that are stable over a variety of temperatures for extended time periods (page 1, Abstract; page 26, lines 32-35). Park teaches concentrations for succinate (0.1-100mM), concentrations for surfactants (e.g. 0.001%-0.5% polysorbate 80), concentrations for sucrose (0.05-10%), ranges for pH (5.0-8.0), and other excipients and/or adjuvants that may be added to protein formulations to improve stability (§Formulations starting from page 10, line 5-page 33, line 32). Additionally, Park teaches that the concentration of protein is between about 1mg/ml and 10mg/ml or at a concentration of about 2mg/ml (page 24, line 19 – page 26, line 13).
Regarding instant claims 10, 69, and 113, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence SEQ ID NO:132 with the secretory signal sequence SEQ ID NO:198, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising HCDR1-3 comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 (which is the CD3 binding domain of amino acid sequence SEQ ID NO:132) comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
as taught by the combined teachings of Tan and Hernandez-Hoyos to include that the composition comprises about 2mg/ml of the multispecific protein as taught by Park. This is obvious because, the combined teachings of Tan and Hernandez-Hoyos teach a composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence SEQ ID NO:132 with the secretory signal sequence SEQ ID NO:198, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising HCDR1-3 comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 (which is the CD3 binding domain of amino acid sequence SEQ ID NO:132) comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
and Park teaches methods of making solid and liquid protein formulations that are stable over a variety of temperatures for extended time periods, wherein the concentration of protein comprising the protein formulation is at a concentration of about 2mg/ml. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO 31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the amino acid sequence instant SEQ ID NO:18 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:10-12, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:134 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:13-15, respectively;
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:19-21, respectively, and a VL comprising the amino acid sequence instant SEQ ID NO:384 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:22-24, respectively; and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
wherein the instant composition comprises about 2mg/ml of the instant multispecific fusion protein.
Claims 111-112 are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan) and Hernandez-Hoyos (Hernandez-Hoyos et al, WO2018057802A1, Priority to 9/21/2016, Published on 3/29/2018, IDS entered on 5/12/2023; hereinafter Hernandez-Hoyos) as applied to claims 1, 67, and 108 above, and further in view of Blankenship (Blankenship et al, US20170306045A1, Priority to 4/22/2011, Published on 10/26/2017; hereinafter Blankenship).
Regarding instant claims 111-112, the combined teachings of Tan and Hernandez-Hoyos are discussed above.
Hernandez-Hoyos further teaches that the hinge region of the CD123 binding polypeptide comprising two binding regions comprises the amino acid sequence SEQ ID NO:226 (pages 51-52, ¶ [00153], Table 1), which is identical to the claimed hinge sequence of instant SEQ ID NO:47 recited in instant claims 111 and 112.
However, the combined teachings of Tan and Hernandez-Hoyos do not teach the composition comprising a multispecific protein and a formulation buffer wherein the multispecific protein comprises an immunoglobulin constant region comprising the amino acid sequence instant SEQ ID NO:131, and a Fc-binding domain linker comprising the amino acid sequence instant SEQ ID NO:132.
The deficiency is resolved by Blankenship.
Blankenship teaches multispecific polypeptide therapeutics that specifically target cells expressing prostate-specific membrane antigen (PSMA) that are useful for the treatment of prostate cancer or tumor-related angiogenesis. (page, Abstract). Blankenship also teaches that the PSMA-binding polypeptide comprises an immunoglobulin constant region comprising immunoglobulin CH2 and CH3 domains of IgG1 comprising the amino acid sequence SEQ ID NO:42 (page, ¶ [0013]-[0014]). SEQ ID NO:42 is identical to instant SEQ ID NO:131. Additionally, Blankenship teaches the Fc-binding domain linker (linker H98) comprising SEQ ID NO:68 (SSLNTGTQPNS) in the sequence listing as an exemplary linker among other linker sequences, wherein SEQ ID NO:68 is identical to instant SEQ ID NO:132.
Regarding instant claim 111-112, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence SEQ ID NO:132 with the secretory signal sequence SEQ ID NO:198, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising HCDR1-3 comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 (which is the CD3 binding domain of amino acid sequence SEQ ID NO:132) comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
as taught by the combined teachings of Tan and Hernandez-Hoyos to include that the composition comprises a hinge region comprising amino acid sequence SEQ ID NO:226 of Hernandez-Hoyos, an immunoglobulin constant region comprising amino acid sequence SEQ ID NO:42, and a Fc-binding domain linker comprising amino acid sequence SEQ ID NO:68 as taught by Blankenship. This is obvious because, the combined teachings of Tan and Hernandez-Hoyos teach a composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence SEQ ID NO:132 with the secretory signal sequence SEQ ID NO:198, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising HCDR1-3 comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 (which is the CD3 binding domain of amino acid sequence SEQ ID NO:132) comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
Hernandez-Hoyos teaches that the hinge region of the CD123 binding polypeptide comprising two binding regions comprises the amino acid sequence SEQ ID NO:226, and Blankenship teaches a multispecific polypeptide therapeutic comprising an immunoglobulin constant region comprising immunoglobulin CH2 and CH3 domains of IgG1 comprising the amino acid sequence SEQ ID NO:42, and an Fc-binding domain linker (linker H98) comprising SEQ ID NO:68. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO 31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the amino acid sequence instant SEQ ID NO:18 comprising: (i) a VH comprising the amino acid sequence instant SEQ ID NO:136 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:10-12, respectively; and a VL comprising the amino acid sequence instant SEQ ID NO:134 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:13-15, respectively;
A hinge region comprising amino acid sequence instant SEQ ID NO:47
An immunoglobulin constant region comprising amino acid sequence instant SEQ ID NO:131,
A Fc-binding domain linker comprising amino acid sequence instant SEQ ID NO:132, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising (i) a VH comprising the amino acid sequence instant SEQ ID NO:383 comprising HCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:19-21, respectively; and a VL comprising the amino acid sequence instant SEQ ID NO:384 comprising LCDR1-3 comprising the amino acid sequences instant SEQ ID NOs:22-24, respectively; and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
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.
Provisional
Claims 1, 4, 17-19, 21, 26, 67, and 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 9,745,381B2 (hereinafter ‘381) in view of Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan).
Regarding instant claims 1, 18-19, 21, 26, 67, and 75, claim 1 of ‘381 teach a homodimer that specifically binds CD123 and CD3, wherein said homodimer comprises a polypeptide comprising a target binding domain that specifically binds CD123, an effector binding domain that specifically binds CD3, and an immunoglobulin constant region linker operatively coupling the target binding domain and the effector binding domain. Regarding instant claims 17 and 75, claim 5 of ‘381 further teach that the immunoglobulin constant region of the homodimer is a human IgG constant region. The disclosure of ‘381 also teaches that the binding domains are linked using a hinge-CH2-CH3 domain or a hinge-CH3 domain of human IgG1 constant region as a linker (page 12, column 3, second paragraph). Furthermore, regarding instant claim 4, the disclosure of ‘381 teaches pharmaceutical compositions comprising the homodimer, wherein adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents may also be included in the composition (page 17, column 14 – page 18, column 16, §IV. Pharmaceutical Compositions and Administration Thereof).
However, ‘381 does not teach a composition comprising a multispecific protein, a buffer, an excipient, and a surfactant, wherein the buffer comprises succinate or a pharmaceutically acceptable salt or acid thereof.
The deficiency is resolved by Tan.
The teachings of Tan are discussed above in the 102 rejection.
Regarding instant claims 1, 4, 17-19, 26, 67, and 75, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the composition comprising a multispecific protein comprising a homodimer that specifically binds CD123 and CD3, wherein an immunoglobulin constant region linker comprising a human IgG constant region comprising the structure hinge-CH2-CH3 operatively couples the target binding domain and the effector binding domain as taught by ‘381 to include that the composition includes a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 as taught by Tan. This is obvious because, ‘381 teaches a pharmaceutical composition comprising a homodimer that specifically binds CD123 and CD3, wherein said homodimer comprises a polypeptide comprising a target binding domain that specifically binds CD123, an effector binding domain that specifically binds CD3, and an immunoglobulin constant region linker comprising a human IgG1 constant domain comprising the structure hinge-CH2-CH3 operatively couples the target binding domain and the effector binding domain, wherein the pharmaceutical composition also includes adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents, and Tan teaches multispecific proteins comprising a tumor antigen (e.g. CD123) binding domain and a CD3 binding domain, wherein the multispecific proteins are diluted in a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 for stability and prevention of protein loss. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising a multispecific protein, a buffer, an excipient, and a surfactant, wherein:
The multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain that specifically binds CD123,
A hinge region,
An immunoglobulin constant region, and
A second binding domain that specifically binds to CD3; and
the buffer comprises succinate,
wherein the composition comprises 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
Claims 1, 18-19, 21, 26, 42-48, 67, 93-100, 106, and 108-110 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of U.S. Patent No. 10,676,533B2 (hereinafter ‘533) in view of Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan).
Regarding instant claims 1, 18-19, 21, 26, 42-48, 67, 93-100, 106, and 108-110, claim 1 of ‘533 teaches a method for treating a disorder in a subject, wherein said disorder is characterized by overexpression of CD123, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant polypeptide comprising a CD123 binding domain and a CD3 binding domain, wherein: (i) the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO:132; and (ii) the administration of the pharmaceutical composition induces reduced cytokine levels in the subject as compared to administration of a bispecific T-cell engager molecule comprising the CD123 binding domain and the CD3 binding domain of the recombinant polypeptide. Claim 6 of ‘533 further teaches that the pharmaceutical composition comprises a dimeric protein comprising two identical copies of the recombinant polypeptide. ‘533 also teaches that in certain variations, a secretory signal sequence can be used use in accordance with the present disclosure comprising the amino acid sequence MEAPAQLLFLLLLWLPDTTG (SEQ ID NO:198) (page 74 of ‘533 specification, column 96, third paragraph). SEQ ID NO:198 included in SEQ ID NO:132 is identical to instant SEQ ID NO:31.
However, ‘533 does not teach a composition comprising a multispecific protein, a buffer, an excipient, and a surfactant, wherein the buffer comprises succinate or a pharmaceutically acceptable salt or acid thereof.
The deficiency is resolved by Tan.
The teachings of Tan is discussed above in the 102 rejection.
Regarding instant claims 1, 18-19, 26, 42-48, 67, 93-100, and 106, and 108-110, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify pharmaceutical composition comprising a recombinant polypeptide comprising a CD123 binding domain and a CD3 binding domain, wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO:132 as taught by ‘533 to include that the composition includes a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 as taught by Tan. This is obvious because, ‘533 teaches a pharmaceutical composition comprising a recombinant polypeptide comprising a CD123 binding domain and a CD3 binding domain, wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO:132, and Tan teaches multispecific proteins comprising a tumor antigen (e.g. CD123) binding domain and a CD3 binding domain, wherein the multispecific proteins are diluted in a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 for stability and prevention of protein loss. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising a multispecific protein, a buffer, an excipient, and a surfactant, wherein:
The multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain that specifically binds CD123,
A hinge region,
An immunoglobulin constant region, and
A second binding domain that specifically binds to CD3;
wherein each polypeptide comprises the amino acid sequence instant SEQ ID NO:31; and
the buffer comprises succinate,
wherein the composition comprises 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
Furthermore, regarding instant claims 1, 42-48, 67, 93-100, 106, and 108-110 (composition claims), the method of treating as claimed in ‘533 is comprised of administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant polypeptide comprising a CD123 binding domain and a CD3 binding domain, wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO:132, which is the same as the instant claimed composition comprising a multispecific protein, wherein the multispecific protein is a dimer of two identical polypeptides, wherein each polypeptide comprises the amino acid sequence SEQ ID NO:31. A claimed product is obvious over a patented method comprising the product. Therefore, although the claims at issue are not identical, the instant claims are not patentably distinct from the issue claims.
Claims 1, 17-19, 21, 26, 34-36, 38-40, 42-48, 53-54, 67, 75-77, 85-87, 89-91, 93-100, 106, and 108-110 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-12, 14-23 and 33 of U.S. Patent No. 11,242,400B2 (hereinafter ‘400) in view of Tan (Tan et al, US20180273622A1, Priority to 9/21/2015, Published on 9/27/2018, IDS entered on 5/1/2024; hereinafter Tan) and Albrecht et al (WO2018015340A1, priority to July 18, 2016; hereinafter Albrecht).
Regarding instant claims 1, 17-19, 21, 26, 34, 42-48, 67, 85, 93-100, 106, and 108-110, claims 11, 16, 21-22, and 33 of ‘400 teach a pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises, in order from amino terminus to carboxyl terminus, (i) a CD123-binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl-terminus linker, and (v) a CD3-binding domain comprising amino acid sequence SEQ ID NO:312, wherein the CD123-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:2; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and the CD3-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:158; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159. SEQ ID NOs:132, 2, 4, 159, and 312 are identical to instant SEQ ID NOs:31, 134, 136, 383, and 27, respectively. Regarding instant claims 35-36, 38-40, 86-87, and 89-91, claims 12 and 17-18 of ‘400 teach that the CD123-binding domain is an scFv comprising a immunoglobulin VL region, an immunoglobulin VH region, and a peptide linker joining the VL and VH regions comprising the amino acid sequence comprising (Gly4Ser)n, wherein n=1-5 (SEQ ID NO:214), and the CD3-binding domain is an scFv comprising a immunoglobulin VL region, an immunoglobulin VH region, and a peptide linker joining the VL and VH regions comprising the amino acid sequence comprising (Gly4Ser)n, wherein n=1-5 (SEQ ID NO:214). Regarding instant claims 53-54 and 75-77, claims 14 and 15 of ‘400 teach that the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, wherein the immunoglobulin constant region comprises a human IgG1 CH2 domain comprising the substitutions L234A, L235A, G237A, and K322A, according to the EU numbering system. Claims 19 and 20 of ‘400 teach that the carboxyl-terminus linker comprises an amino acid sequence comprising (Gly4Ser)n, wherein n=3-5. Furthermore, claim 23 teaches an isolated nucleic acid molecule encoding the recombinant polypeptide.
However, ‘400 does not teach a composition comprising a multispecific protein comprising a CD3 binding domain comprising a VL comprising the amino acid sequence instant SEQ ID NO:384, a buffer, an excipient, and a surfactant, wherein the buffer comprises succinate or a pharmaceutically acceptable salt or acid thereof.
The deficiency is resolved by Tan and Albrecht.
The teachings of Tan is discussed above in the 102 rejection. The teachings of Albrecht are discussed above in the 112(a) rejection.
Regarding instant claims 1, 18-19, 26, 34, 42-48, 67, 85, 93-100, 106, and 108-110, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises, in order from amino terminus to carboxyl terminus, (i) a CD123-binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl-terminus linker, and (v) a CD3-binding domain comprising amino acid sequence SEQ ID NO:312, wherein the CD123-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:2; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and the CD3-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:158; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159 as taught by ‘400 to substitute SEQ ID NO:158 with instant SEQ ID NO: 384 as taught by Albrecht and also include that the composition includes a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 as taught by Tan. This is obvious because, ‘400 teach a pharmaceutical composition comprising a polypeptide and pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises, in order from amino terminus to carboxyl terminus, (i) a CD123-binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl-terminus linker, and (v) a CD3-binding domain comprising amino acid sequence SEQ ID NO:312, wherein the CD123-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:2; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and the CD3-binding domain comprises an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:158; and an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:159 (SEQ ID NOs:2, 4, 159, and 312 are identical to instant SEQ ID NOs:134, 136, 383, and 27, respectively), Tan teaches multispecific proteins comprising a tumor antigen (e.g. CD123) binding domain and a CD3 binding domain, wherein the multispecific proteins are diluted in a formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8 for stability and prevention of protein loss, and Albrecht teaches that introducing mutations in the backbone without altering the CDRs did not cause any changes in binding kinetics to CD3 and CD123, did not cause any loss of activity in T-cell engaging, and did not induce unwanted effects in regard to T-cell activation in the absence of target cells. In this context, there was only a single amino acid difference in SEQ ID NO:158 of ‘400 compared to the instantly claimed amino acid sequence SEQ ID NO:384 comprising the VL region of the CD3 binding domain, wherein the difference occurred in the framework region as shown below.
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Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein that is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO:31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136, and a VL comprising the amino acid sequence instant SEQ ID NO:134,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383, and a VL comprising the amino acid sequence instant SEQ ID NO:384, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
Regarding instant claims 17, 53-54, and 75-77, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises:
a multispecific protein that is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
as taught by the combined teachings of ‘400, Tan, and Albrecht to include that the immunoglobulin constant region further comprises IgG1 CH2 and CH3 domains wherein the human lgG1 Fc domain has L234A, L235A, G237A, and K322A mutation (according to the EU numbering system) as taught by ‘400. This is obvious because, the combined teachings of ‘400, Tan and Albrecht teach pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises:
a multispecific protein that is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
and ‘400 teaches that the immunoglobulin constant region of the multispecific protein comprises CH2 and CH3 domains of IgG1, wherein the lgG1 CH2 domain comprises L234, L235, G237, and K322 (according to EU numbering) mutated to an alanine (i.e., L234A, L235A, G237A, and K322A, respectively). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein that is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO:31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136, and a VL comprising the amino acid sequence instant SEQ ID NO:134,
A hinge region,
An immunoglobulin constant region comprising IgG1 CH2 and CH3 domains of IgG1, wherein the IgG1 CH2 domain comprises the substitutions L234A, L235A, G237A, and K322A according to EU numbering, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383, and a VL comprising the amino acid sequence instant SEQ ID NO:384, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8.
Regarding instant claims 35-36, 38-40, 86-87, and 89-91, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises:
a multispecific protein that is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
as taught by the combined teachings of ‘400, Tan, and Albrecht to include that the first and second binding domains are scFvs a linker peptide between the VL and VH of the scFv, wherein the linker peptide comprises a Gly4Ser linker. This is obvious because, the combined teachings of ‘400, Tan and Albrecht teach pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the polypeptide comprises a dimer comprising two identical recombinant polypeptides, wherein the recombinant polypeptide comprising amino acid sequence SEQ ID NO:132 comprises:
a multispecific protein that is a dimer of two identical polypeptides, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising the CD123 binding domain of the amino acid sequence instant SEQ ID NO:132 comprising a VH comprising the amino acid sequence instant SEQ ID NO:4, and a VL comprising LCDR1-3 comprising the amino acid sequence instant SEQ ID NO:2,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 scFv that specifically binds CD3 comprising the amino acid sequence SEQ ID NO:312 comprising a VH comprising HCDR1-3 comprising the amino acid sequence SEQ ID NO:159, and a VL comprising LCDR1-3 comprising the amino acid sequence SEQ ID NO:157, and
5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
and ‘400 teaches that the recombinant CD123-binding polypeptides comprise CD123-binding and CD3-binding scFvs comprising a peptide linker between the VH and VL in the scFv, wherein the peptide linker comprises the amino acid sequence Gly4Ser. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition comprising:
a multispecific protein that is a dimer of two identical polypeptides, each polypeptide comprising the amino acid sequence instant SEQ ID NO:31, wherein each polypeptide comprises, in order from amino terminus to carboxyl terminus:
A first binding domain comprising an anti-CD123 scFv that specifically binds CD123 comprising a VH comprising the amino acid sequence instant SEQ ID NO:136, and a VL comprising the amino acid sequence instant SEQ ID NO:134,
A hinge region,
An immunoglobulin constant region, and
A second binding domain comprising an anti-CD3 that specifically binds CD3 comprising the amino acid sequence instant SEQ ID NO:27 comprising a VH comprising the amino acid sequence instant SEQ ID NO:383, and a VL comprising the amino acid sequence instant SEQ ID NO:384, and
formulation buffer comprising 5mM succinate, 6.5% sucrose, and 0.02% Tween80 at a pH of 4.8,
wherein, the first and second binding domains are scFvs comprising a linker peptide between the VL and VH of the scFv, wherein the linker peptide comprises the sequence Gly4Ser (instant SEQ ID NO:128.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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