Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 32-39 are cancelled.
Claims 1-31 and 40-46 are pending.
Applicant’s election without traverse of Group I, claims 1-31 and 46, in the reply filed on 05/19/2026 is acknowledged. Applicant’s election without traverse of the species of:
1. As the single set of 6 CDRs that bind VEGF indicating the HCVR, LCVR, HC, and LC sequences the following:
VEGF SEQUENCE ELECTIONS:
i. VH CDR1, 2, and 3: SEQ ID NO: 148, 149 and 150;
ii. VL CDR1, 2, and 3: SEQ ID NO: 145, 146, 147;
iii. VH SEQ ID NO: 191;
iv. VL: SEQ ID NO: 193;
V. HC SEQ ID NO: 197; and
vi. LC: SEQ ID NO: 199;
2. As the single set of 6 CDRs that bind TRKB indicating the HCVR, LCVR, HC, and LC
sequences the following:
TrkB SEQUENCE ELECTIONS:
i. VH CDR1, 2, and 3: SEQ ID NO: 204, 205 and 206;
ii. VL CDR1, 2, and 3: SEQ ID NO: 201, 202 and 203;
iii. VH SEQ ID NO: 214;
iv. VL: SEQ ID NO: 213; and
V. scFv: SEQ ID NO: 222.
3. As the single antibody format:
Bispecific tetravalent Doppelmab (IgG part binds VEGF; two scFvs which bind TrkB attached to the C-Terminus of the IgG).
in the reply filed on 05/19/2026 is acknowledged. Where SEQ ID NO: 222 has been searched and deemed to be free from the prior art the restriction of species of anti-TrkB scFv between SEQ ID NOs: 222, 223, 224, and 225 is withdrawn. Additionally, upon further consideration, the restriction between species of antibody format is withdrawn.
Claims 30-31 and 40-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/19/2026.
Claims 1-29 and 46 are under examination on the merits.
Priority
This application is a DIV of US Patent Application No.17/505,672 filed 10/20/2021 (issued as US Patent No. 12,110,335), which claims benefit of priority to EP 20203030.0, filed 10/21/2020. Priority documents were electronically retrieved by the USPTO in the parent US Patent Application No.17/505,672.
IDS
The information disclosure statements (IDS’) filed 05/19/2026 have been considered.
Claim Objections
Claim 15 is objected to because of the following informalities: there is no connecting term between options a, b, and c. In the interest of advancing prosecution, the claim is being interpreted as reciting “and” between options a, b, and c given the drafting of the claim reciting options a, b, and c as members of a Markush group.
Claim 16 is objected to because of the following informalities: there is no connecting term between options a, b, c, and d. In the interest of advancing prosecution, the claim is being interpreted as reciting “and” between options a, b, c, and d given the drafting of the claim reciting options a, b, c, and d as members of a Markush group.
Claim 17 is objected to because of the following informalities: there is no connecting term between options a, b, c, and d. In the interest of advancing prosecution, the claim is being interpreted as reciting “and” between options a, b, c, and d given the drafting of the claim reciting options a, b, c, and d as members of a Markush group.
Claim 18 is objected to because of the following informalities: there is no connecting term between options for the light chain SEQ ID NOs. In the interest of advancing prosecution, the claim is being interpreted as reciting “or” between options of alternatively recited light chain SEQ ID NOs. Likewise, there is no connecting term between options for the heavy chain SEQ ID NOs. In the interest of advancing prosecution, the claim is being interpreted as reciting “or” between options of alternatively recited heavy chain SEQ ID NOs.
Claim 29 is objected to for its dependence from rejected base claim 28, but would be allowable if drafted into independent form.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-18, 20-27, and 46 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.
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. 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. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antibodies by impermissibly allowing variation within the CDRs without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses antibodies/fragments thereof against VEGF and/or TrkB are known in the art (see page 1 at paragraph 0004, pages 3-12, paragraph 0169at page 46, Table 1 ranging pages 53-88, paragraph 00200 at page 88, Table 2 ranging pages 88-92, see pages 125-126 discussing Venkataramani et al and Table 3, as exemplary), but only provides examples having 100% identity to the recited CDRs and certain paired VH and VL sequences (for example, SEQ ID NO: 1 (a light chain) is not clearly paired with any other sequence/ heavy chain other than SEQ ID NO: 2) and does not provide evidence that the claimed sequences with the claimed degree of mutations (for example, wholly different LCDRs/HCDRs via VH/VL interchangeability or 80% mutation in the VH or VL, all of which may be in the CDRs) would function to bind as claimed. While Applicant provides many examples, the examples provided in no way are representative of the degree of mutation permitted (the breadth of binding molecules claimed) and does not identify a structure function correlation clearly required for the functions claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies or of CDRs binding VEGF and/or TrkB as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing any mutations or not) might be included in the genus.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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. Applicant has only fully disclosed sets of 6 CDRs having 100% homology to the claimed SEQ ID NOs and or fragments having 100% homology to the claimed SEQ ID NOs for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only species having 100% homology is not sufficiently representative of the entire genus claimed (encompassing CDRs not described or even invented and/or multiple combinations of mutations in the CDRs/interchangeability of HCDRs and LCDRs).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid/binding sequences that confer upon an antibody/fragment thereof the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with a functional ability to function.
Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, 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. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind VEGF and/or TrkB. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind VEGF and/or TrkB, as claimed. Thus, the claims need to specify exact CDR sequence combinations of the claimed binding molecules.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody binding generally, binding TrkB, binding VEGF, or binding VEGF and TrkB in a bispecific format. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides disclosure of antibodies/fragments thereof having 100% identity to the claimed SEQ ID NOs, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad scope recited in the claims by Applicant. The specification does not disclose the structure of all of the claimed variant antibodies and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims. Moreover, the state of the art does not support interchangeability of light and heavy chains (see for example, WO 2008068048 A2).
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also 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.”
Regarding claim 12, the claim depends from claim 1 which recites a bispecific binding agent binding TRKB and VEGF. While claim 12 provides adequate written description of the TrkB binding site, there is no written description for the full binding agent encompassed because the VEGF binding agent is not described (can be any agent, including binding sites (CDRs) yet to be invented). Therefore, claim 12 is included in this rejection.
Regarding claim 14, the claim depends from claim 1 which recites a bispecific binding agent binding TRKB and VEGF. While claim 14 provides adequate written description of the TrkB binding site, there is no written description for the full binding agent encompassed because the VEGF binding agent is not described (can be any agent, including binding sites (CDRs) yet to be invented). Therefore, claim 14 is included in this rejection.
Regarding claim 15, the claim depends from claim 1 which recites a bispecific binding agent binding TRKB and VEGF. While claim 15 provides adequate written description of the VEGF binding site, there is no written description for the full binding agent encompassed because the TrkB binding agent is not described (can be any agent, including binding sites yet to be invented). Therefore, claim 15 is included in this rejection.
Thereby, the antibodies, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 1-18, 20-27, and 46 are deemed to fail to meet the written description requirement, as presently drafted.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-6, 8-11, and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH (WO2018224630A1, published 12/13/2018) in view of Hoffman (WO2010040508 A1).
Regarding claim 1, Gmbh teaches an anti-TrkB antibody/fragment thereof (see paragraph 0001) for age-related macular degeneration or other disease of the eye (see for example, paragraph 0006 at page 2; the fragment thereof may be an scFv (see for example, paragraphs 0062 and 0066 at pages 15-16 and claim 1 at page 97) that may be combined, “as an add-on to anti-VEGF treatment which will greatly enhance the therapeutic benefits of the latter since anti-VEGF targets only vascular dysfunction in the eye but not the neuron/glial cells system; in addition, long-term anti-VEGF treatment might cause neurodegenerative side-effects. A TrkB activating approach as an add-on to anti-VEGF will reduce such neurodegenerative side-effect,” (see paragraph 00233 at page 62). Gmbh further teaches that “the anti-TrkB antibody or antigen-binding fragment thereof can be co-administered in combination with one or more therapeutic agents for the treatment or prevention of a TrkB-related disease. For example, combination therapy can include anti-VEGF, anti- PDGF, or anti-ANG2,” (see paragraph 00259 at page 67).
Hoffman teaches VEGF antibodies for age-related macular degeneration (including the wet subtype) in the format of a bispecific antibody that also binds ang-2 (see for example, pages 1-2).
It would have been prima facie obvious to combine anti-TrkB antibodies/scFvs, such as those taught in Gmbh with anti-VEGF antibodies, such as those taught in Hoffman, into a bispecific antibody for age-related macular degeneration because 1) Gmbh teaches the desirability of combining anti-TrkB antibodies with anti-VEGF treatments, as discussed above, an 2) because the MPEP provides that:
“"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980),”
(see MPEP section 2144.06(I)). Combining the anti-TrkB binding moieties (such as scFvs) of GmbH and the anti-VEGF binding moieties of Hoffman into a bispecific format known in the art, such as the bispecific, tetravalent format of Hoffman would have been obvious in order to achieve an effective combination of the two moieties taught to be individually effective for treating macular degeneration, with a reasonable expectation of success, prior to the effective filing date.
Regarding claim 2, the primary difference of claim 2 over claim 1 is that claim specifies a tetravalent, bispecific format. Hoffman teaches a bispecific, tetravalent antibody format and teaches that many such antibodies have been previously developed. A wide variety of recombinant antibody formats have been developed in the recent past, e.g. tetravalent bispecific antibodies by fusion of, e.g., an IgG antibody format and single chain domains (see for example, pages 8-9).
Regarding claims 3-4 and 10, Hoffman teaches a wide variety of recombinant antibody formats have been developed in the recent past, e.g. tetravalent bispecific antibodies by fusion of, e.g., an IgG antibody format and single chain domains (see for example, pages 8-9, page 16, and page 36). Hoffman further teaches that in certain embodiments, antibodies of the invention further comprise immunoglobulin constant regions of one or more immunoglobulin classes, including IgG where in a preferred embodiment, an antibody of the invention has a constant domain structure of an IgG type antibody, but has four antigen binding sites. This is accomplished e.g. by linking two complete antigen binding sites (e.g., a single chain Fv) specifically binding to VEGF to either to N- or C-terminus heavy or light chain of a full antibody specifically binding to ANG-2. Alternatively this is accomplished by fusing two complete binding peptides specifically binding to ANG-2 to either to C-terminus heavy chain of a full antibody specifically binding to VEGF. The four antigen-binding sites preferably comprise two antigen-binding sites for each of two different binding specificities (see for example, pages 28-29).
Regarding claims 5-6 and 8, as discussed above, Hoffman et al teach a bispecific, tetravalent antibody format accomplished by fusing two complete binding peptides specifically binding to ANG-2 to either to C-terminus heavy chain of a full antibody specifically binding to VEGF. The four antigen-binding sites preferably comprise two antigen-binding sites for each of two different binding specificities (see for example, pages 28-29).
It would have been prima facie obvious to the artisan, looking to make a bispecific antibody binding VEGF and TrkB to treat macular degeneration, to substitute the TrkB scFvs taught by GmbH in place of the two Ang-2-binding scFvs of Hoffman to arrive at a bispecific, tetravalent antibody binding VEGF and TrkB to treat macular degeneration with a reasonable expectation of success prior to the effective filing date because this format is known in the art and it taught to be a viable bispecific format.
Regarding claim 9, Hoffman teaches a wide variety of recombinant antibody formats have been developed in the recent past, e.g. tetravalent bispecific antibodies by fusion of, e.g., an IgG antibody format and single chain domains (see for example, pages 8-9, page 16, and page 36). Hoffman further teaches that in certain embodiments, antibodies of the invention further comprise immunoglobulin constant regions of one or more immunoglobulin classes, including IgG where in a preferred embodiment, an antibody of the invention has a constant domain structure of an IgG type antibody, but has four antigen binding sites. This is accomplished e.g. by linking two complete antigen binding sites (e.g., a single chain Fv) specifically binding to VEGF to either to N- or C-terminus heavy or light chain of a full antibody specifically binding to ANG-2. Alternatively this is accomplished by fusing two complete binding peptides specifically binding to ANG-2 to either to C-terminus heavy chain of a full antibody specifically binding to VEGF(see for example, pages 28-29). Hoffman teaches several anti-VEGF monoclonal antibodies (such as bevacizumba (humanized monoclonal) and ranibizumab (a monoclonal antibody fragment)) either of which would have been obvious to adapt to make a bispecific antibody having the format of Hoffman with a reasonable expectation of success as a known anti-VEGF for treating macular degeneration when combined with an anti-TrkB in a bispecific format known in the art.
Regarding claim 11, Hoffman teaches that a variety of bispecific formats have been developed in the art, where all such formats (such as IgG antibody core fusion to one or more scFvs) use linkers (see for example, page 10). The term "peptide-linker" as used within the invention denotes a peptide with amino acid sequences, which is preferably of synthetic origin. These peptide linkers according to invention are used to link the different antigen-binding sites and/or antibody fragments eventually comprising the different antigen-binding sites (e.g. single chain Fv, full length antibodies, a VH domain and/or a VL domain, Fab, (Fab)2, Fc part) together to form a bispecific antibody according to the invention The peptide-linkers can comprise one or more of the following amino acid sequences listed in Table 1 as well as further arbitrarily selected amino acids. In one embodiment said peptide-linker is (GxS)n with G = glycine, S = serine, (x = 3 and n= 3, 4, 5 or 6) or (x = 4 and n= 2, 3, 4 or 5), preferably x = 4 and n= 2 or 3, 5 more preferably with x = 4, n= 2 ((G4S)z). To said (GxS)n peptide-linker also additional G = glycines can be added, e.g. GG, or GGG (see for example, pages 38-39).
Regarding claim 46, Hoffman teaches pharmaceutical compositions containing antibodies bispecific for VEGF and ANG-2 (see for example, the abstract at cover page, paragraph 1 at page 1, page 16 bridging page 17, the final paragraph at page 48, and claims 11-14 at page 116).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to provide the a bispecific molecule binding VEGF and TrkB for treating macular degeneration in a format ready for administration to a subject suffering from macular degeneration. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH in view of Hoffman, as applied to claims 1-6, 8-11, and 46 above, in further view of Lin et al (US2010196390A1).
Regarding claim 12, as discussed above, GmbH and Hoffman teach and make obvious the binding molecule of instant claim 1.
The combined references do not teach LCDRs1-3 having a sequence as shown in instant SEQ ID NOs: 201, 202, and 203 and/or HCDRs1-3 having a sequence as shown in instant SEQ ID NOs: 204, 205, and 206.
However, Lin et al teach anti-TrkB antibodies (see for example, the abstract and claim 1), said antibodies having a VL region comprising the amino acid sequence shown in SEQ ID NO: 173 which comprises sequences identical to SEQ ID NOs: 201, 202, and 203 in the form of LCDRs1-3 (see the alignment provided below).
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Lin et al additionally teach that the VL of SEQ ID NO: 173 is paired with a VH of SEQ ID NO: 12, said VH region comprising sequences identical to SEQ ID NOs: 204, 205, and 206 in the form of HCDRs1-3 (see the alignment provided below) (see for example, claims 1 and 6 and paragraph 0023 at page 3 and 128-129). Lin et al also teach scFvs (see for example, paragraph 0166 at page 36) (see the alignment below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the TrkB binding moiety of Lin et al would have been an obvious functional equivalent for the TrkB binding moiety of GmbH. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic bispecific antibody capable of binding TrkB to treat macular degeneration (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 13, Lin et al teach an anti-TrkB having a VH of SEQ ID NO: 12, which is 98.2% identical to instantly claimed SEQ ID NO: 214 (see for example, claims 1 and 6 of Lin et al and the alignment, below).
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Lin et al further teach that an anti-TrkB having a VL of SEQ ID NO: 173, which is 97.9% identical to instantly claimed SEQ ID NO: 213 (see for example, claims 1 and 6 of Lin et al and the alignment, below).
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Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH in view of Hoffman, as applied to claims 1-6 and 8-11 above, in further view of Hewitt et al (AU2016213727A1).
Regarding claim 15, GmbH and Hoffman teach and make obvious the binding molecule of instant claim 1.
The combined references do not teach the instantly claimed LCDR1-3 and HCDR1-3 sequences.
However, Hewitt et al teach a therapeutic antibody that binds to VEGF. The anti-VEGF antibody may, for example, comprise a heavy and/or light chain variable domain sequence selected from the group consisting of SEQ ID NOS: 20 through 25 (See for example, paragraph 3 of page 5).
SEQ ID NO: 25 of Hewitt et al comprises sequences identical to instant CDR sequences: 148, 149, and 150 (see for example, the alignment below).
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SEQ ID NO: 20 of Hewitt et al comprises sequences identical to instant CDR sequences: 145, 146, and 147 (see for example, the alignment below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the VEGF binding moiety of Hewitt et al would have been an obvious functional equivalent for the VEGF binding moiety of Hoffman. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic bispecific antibody capable of binding VEGF to treat macular degeneration (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH in view of Hoffman, as applied to claims 1-6 and 8-11 above, in further view of Lowman et al (WO 2006031370 A2).
Regarding claim 16, Lowman et al teach an antibody that binds VEGF and comprises the VL of SEQ ID NO: 11 and the VH of SEQ ID NO: 12 (see for example, claim 19). SEQ ID NO: 12 is 99.6% identical to instant SEQ ID NO: 191 (see alignment below).
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SEQ ID NO: 11 is 98.8% identical to instant SEQ ID NO: 193 (see alignment below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the VEGF binding moiety of Lowman et al would have been an obvious functional equivalent for the VEGF binding moiety of Hoffman. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic bispecific antibody capable of binding VEGF to treat macular degeneration (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH in view of Hoffman, as applied to claims 1-6 and 8-11 above, in further view of Lu et al (WO 2019200006 A2).
Regarding claim 17, Lu et al teach an anti-VEGF antibody having seq ID NO: 4 which is 99.4% identical to instant SEQ ID NO: 199 (see for example, claims 1-2 and the alignment below).
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Lu et al teach an anti-VEGF antibody having seq ID NO: 7 which is 99.8% identical to instant SEQ ID NO: 197 (see for example, claims 1-2 and the alignment below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the VEGF binding moiety of Lu et al would have been an obvious functional equivalent for the VEGF binding moiety of Hoffman. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an therapeutic bispecific antibody capable of binding VEGF to treat macular degeneration (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable TGA (Lucentis, obtained from” ttps://www.tga.gov.au/sites/default/files/auspar-ranibizumab-141014-pi.pdf, available as of 2014 as evidenced by the Google Screen capture).
Regarding claim 18, TGA teaches the sequence of the light chain and the heavy chain of ranibizumab. The light chain sequence is identical to instant SEQ ID NO: 29 (see the alignment below and page 2 Figure 1b of TGA).
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The heavy chain sequence of ranibizumab as taught by TGA is 99.4% identical to instant SEQ ID NO: 30 (see the alignment below and page 1 Figure 1a of TGA).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of TGA because TGA teaches ranibizumab, a molecule that binds VEGF (such that ranibizumab is a binding molecule as claimed); see page 1 of TGA, for example). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art reference because TGA teaches ranibizumab (brand name Lucentis) has shown efficacy in clinical trials for treating wet AMD, leading the artisan to reasonably believe ranibizumab successfully binds VEGF as therapeutic for wet AMD (see for example, pages 4-6 of TGA).
Claim(s) 7, 20-27, and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over GmbH (WO2018224630A1, published 12/13/2018) in view of Hoffman (WO2010040508 A1) and Brinkmann et al (2017, VOL. 9, NO. 2, 182–212, http://dx.doi.org/10.1080/19420862.2016.1268307).
Regarding claim 7, as discussed above GmbH in view of Hoffman teach and make obvious the bispecific VEGF/TrkB binding molecule of claims 1 and 5.
GmbH and Hoffman do not explicitly state that the one or more scFvs have a VL-VH orientation from N-to-C terminus.
However, Brinkmann et al, discussing a variety of bispecific formats, including tetravalent formats, teach that fusing a scFv to the CH1 of a heavy chain and another scFv to the CL domain of a light chain results in a tetravalent, bispecific antibody (scFv4-Ig) exhibiting four scFv moieties at the N-termini of the constant regions (Fig. 2, box 12). Brinkmann et al teach that this approach was initially applied to generate a bispecific antibody directed against two epitopes on VEGF receptor and subsequently used by the same group to produce an anti-EGFR x anti-IGF1-R bispecific antibody for dual targeting of tumor cells. Brinkmann et al, reviewing the state of the art of bispecific antibody formats, teach that final selection of the antibodies was based on testing scFv in both orientations (VH-VL and VL-VH) and results from SEC-MALS and differential scanning calorimetry assessing thermal stability and monomeric state. Similarly, stability-improved scFvs were used to generate bispecific antibodies targeting different epitopes on IGF-1R, fusing the scFv to either the N- or C-terminus of an IgG (see for example, pages 195-197; see also for example, page 183 at column 2 and figure 1, Figure 2 at page 184, column 2 of page 186-188; column 2 of page 193, and pages 195-199).
It would have been obvious to the artisan, looking to adapt the bispecific, tetravalent format of Hoffman to arrive at an antibody binding VEGF and TrkB to treat macular degeneration, to try known formats in the art, such as the scFv-IgG fusion of Brinkmann et al, where the VL-VH orientation of the scFv attached to the C-terminus of the IgG by fusion or by a flexible linker would have been formats known in the art and obvious to try in the aim of developing an optimized antibody for treating macular degeneration, using the TrkB scFvs of GmbH and the VEGF of Hoffman. The particular orientation of the VH and VL (VH-VL or VL-VH) from the N to C terminus of the one or more scFvs would appear to be result effective variable optimized by the artisan to achieve an optimized bispecific molecule against VEGF and TrkB. Where the N-C terminus is not specified (merely of the scFv, the VEGF portion to which the scFvs are attached, etc.), this recitation is being interpreted to mean the orientation of the scFv relative to the VEGF binding portion (VL attached to the VEGF-binding portion C-terminus). The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Regarding claims 20-21, as discussed above, the combined references make obvious the use of two scFvs binding TrkB, such as the anti-TrkB scFvs of GmbH to an IgG antibody binding VEGF, such as the antibodies of Hoffman et al, to arrive at a bispecific antibody for targeting VEGF and TrkB to treat macular degeneration in an art known format, such as that taught by Brinkman which comprises two scFvs, such as two anti-TrkB scFvs such as the scFvs of GmbH.
Regarding claims 22-23, Hoffman further teaches that in certain embodiments, antibodies of the invention further comprise immunoglobulin constant regions of one or more immunoglobulin classes, including IgG where in a preferred embodiment, an antibody of the invention has a constant domain structure of an IgG type antibody, but has four antigen binding sites. This is accomplished e.g. by linking two complete antigen binding sites (e.g., a single chain Fv) specifically binding to VEGF to either to N- or C-terminus heavy or light chain of a full antibody specifically binding to ANG-2. Alternatively this is accomplished by fusing two complete binding peptides specifically binding to ANG-2 to the C-terminus heavy chain of a full antibody specifically binding to VEGF (see for example, pages 28-29). Hoffman teaches several anti-VEGF monoclonal antibodies (such as bevacizumba (humanized monoclonal) and ranibizumab (a monoclonal antibody fragment)) either of which would have been obvious to adapt to make a bispecific antibody having the format of one of Hoffman (where the scFvs binding TrkB of GmbH would have been attached to the C terminus of the heavy chain of the IgG according to Hoffman) with a reasonable expectation of success as a known anti-VEGF for treating macular degeneration when combined with an anti-TrkB in a bispecific format known in the art.
Regarding claim 24, as discussed above, the combined references teach and make obvious the limitations of instant claim 21. GmbH teaches that a humanized anti-TrkB antibody can be IgG and that a humanized anti-TrkB antibody comprises substantially all of at least one, and typically two, variable domains (such as contained, for example, in Fab, Fab', F(ab')2, Fabc, and Fv fragments) (see for example, paragraphs 0062 and 0070- 0071 at pages 17-18). It may be favorable to use an antibody fragment rather than an intact antibody (see for example, paragraphs 00149 and 00151 at pages 41-42).
It would have been obvious to the artisan, looking to adapt the bispecific, tetravalent format of Hoffman to arrive at an antibody binding VEGF and TrkB to treat macular degeneration, to use a known anti-TrkB, such as the anti-TrkBs of GmbH, where Gmbh teach that it may be favorable to use an IgG fragment over the full antibody. The fragment format chosen (such as a Fab or F(ab’)2 would have been obvious for the artisan to use for attachment to the IgG anti-VEGF of Hoffman in order to arrive at an optimized bispecific agent for binding TrkB and VEGF for treating macular degeneration). Where the claim recites ‘is an IgG, F(ab)…” this is being interpreted to mean that the binding molecule “comprises an IgG, F(ab), or F(ab’)2…” for advancing prosecution in a way that further limits the claim from claim 21 from which claim 24 depends. The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Regarding claim 25, as discussed above, the combined references teach and make obvious the limitations of instant claim 21. Note that Hoffman teaches that the antibody against VEGF may be a full length IgG, which the artisan would understand comprises an Fc region, such that the resulting anti-TrkB and anti-VEGF bispecific binding molecule (being a TrkB binding molecule) would comprise an Fc region.
Regarding claim 26, as discussed above, the combined references make obvious the use of two scFvs binding TrkB, such as the anti-TrkB scFvs of GmbH to an IgG antibody binding VEGF, such as the antibodies of Hoffman et al, to arrive at a bispecific antibody for targeting VEGF and TrkB to treat macular degeneration in an art known format, such as that taught by Brinkman which comprises 2 anti-TrkB scFvs. The resulting binding molecule from combining the teachings and formats of the cited references, particularly Hoffman and Brinkmann et al would result in a tetravalent, bispecific molecule comprising an IgG anti-VEGF (of Hoffman, for example) and 2 anti-TrkB scFvs (of for example, GmbH). The artisan would have found it obvious to modify the binding molecule according to the combined teachings to arrive at a bispecific molecule binding VEGF and TrkB optimized for treating macular degeneration.
Regarding claim 27, Brinkmann et al teach that fusion of an additional binding site to either the heavy or light chain is a simple and straight-forward solution to overcome the random heavy and light chain pairing. It requires, however, that the additional binding site is expressed by a single polypeptide chain, or that the additional binding site is encoded by polypeptide chains that do not interfere with the light chain and heavy chain interaction of the master antibody. ScFv, but also single-domain antibodies and alternative scaffold proteins, are suitable fusion partners. These appended IgG-based molecules have a symmetric architecture and are tetravalent, possessing two binding sites for each antigen, produced by expression of four polypeptide chains (Fig. 1). This approach was first described in 1997 and may take either of an IgG-HC-scFv (CH3-scFv) or F(ab’)2-scFv2 (Hinge-scFv) format. The fusion proteins maintained high expression level, thermostability, and protease resistance. They also maintained Fc effector functions and half-life similar to the parental IgG antibodies. Fusion of the scFvs to either terminus of the light or heavy chain are discussed such that the placement of the scFv would appear to be a design choice yielding no more than predictable results (resulting in a molecule that predictably performs the function of binding to target). A critical issue to be considered for IgG scFv fusion proteins is the linker connecting the scFv moiety to the IgG. The linker has to be stable and ideally flexible, and fusion should not interfere with antigen binding activity of the scFv and the IgG binding site. Fusing the scFv to the C-terminus of either the heavy or light chain keeps the IgG binding site unaffected. Typical linkers used for IgG-scFv fusion proteins are composed of 2 or 3 repeats of G4S. Also other linkers such as a hydrophilic helical linker, e.g., with the sequence SNS(EEAKK)3SNS, have been used to fuse an scFv to the heavy chain C-terminus (see for example, pages 195-196 and Figure 2 at page 184 of Brinkmann et al).
Regarding claim 46, Hoffman teaches pharmaceutical compositions containing antibodies bispecific for VEGF and ANG-2 (see for example, the abstract at cover page, paragraph 1 at page 1, page 16 bridging page 17, the final paragraph at page 48, and claims 11-14 at page 116).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to provide the a bispecific molecule binding VEGF and TrkB for treating macular degeneration in a format ready for administration to a subject suffering from macular degeneration. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 28 is/are rejected under 35 U.S.C. 103 as being unpatentable Lin et al (US2010196390A1) in view of Hoffman (WO2010040508 A1).
Regarding claim 28, Lin et al teach anti-TrkB antibodies (see for example, the abstract and claim 1), said antibodies having a VH of SEQ ID NO: 12, which is 98.2% identical to instantly claimed SEQ ID NO: 214 (see for example, claims 1 and 6 of Lin et al and the alignment, below).
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Lin et al further teach that an anti-TrkB having a VL of SEQ ID NO: 173, which is 97.9% identical to instantly claimed SEQ ID NO: 213 (see for example, claims 1 and 6 of Lin et al and the alignment, below).
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SEQ ID NOs: 174 and 173 of Lin et al vary from the instantly recited sequences at residue 44 of the VH (being a G instead of a C) and residue 100 of the VL (being a Q instead off a C).
Lin et al do not teach a reason to introduce G44C and Q100C mutations into the VH and VL, respectively.
However, Hoffman teaches that, to address the problems with aggregation of bispecific antibodies, disulfide-stabilization of the scFv moieties was applied by introducing single cysteine replacements within VH and VL of the scFv at defined positions (positions VH44/VL100 according to the Kabat numbering scheme) (see for example, page 84 at lines 15-34).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to enhance stability/reduce aggregation of the scFv binding TrkB of Lin et al using the mutations of Hoffman. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
Claim 19 is allowed.
Claims 14 and 29 are free from the art, but are not allowed.
Claims 1-13, 15-18, 20-29, and 46 are not allowed and are subject to the objections and/or rejections presented in this Office Action above.
The antibody/fragment thereof sequences of claims 14, 19, and 29 have been searched and are deemed to be free of the prior art. The closest prior art is GmbH (WO2018224630A1, published 12/13/2018) in view of Hoffman (WO2010040508 A1) (as cited above in the rejections under 35 USC §103) which in combination teach and make obvious a bispecific binding molecule against VAGF and TrkB (GmbH teaching anti-TrkB binding agents and Hoffman teaching anti-VEGF binding sites) for treating macular degeneration.
Antibodies/fragments thereof are under the domain of highly unpredictable art. Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the residues of the binding surface form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This would indicate that the binding residues interact to form the conformation of the paratope such that mutation of one or more of the binding residues/sequences may unpredictably change the paratope topology thereby unpredictably changing binding. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al thus teach that affinity and specificity are not necessarily correlated and that and increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity my lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). This art is deemed applicable given that the instantly claimed peptides bind (similar to antibodies) and encompass antibodies. Therefore, a difference of a single amino acid in the VH or VL domain (binding region(s)) is enough to render an antibody/fragment thereof free of the art.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision the binding-enabling sequences recited in the instant claim 14, 19, and/or 29.
Claim 19 is allowed in light of the absence for reasons for rejection.
Claims 14 and 29 are free from the art, but suffer from deficiencies, as noted above, which preclude their allowance at this time.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wu et al (MAbs. 2015;7(3):470-82. doi: 10.1080/19420862.2015.1022694) is deemed relevant.
Venkataramani et al (Biochem Biophys Res Commun. 2018 Sep 26;504(1):19-24. doi: 10.1016/j.bbrc.2018.08.064) teach that bispecific antibodies that bind to two different targets are attractive formats to enhance the potential of drug delivery and disease treatment. Most challenging factors in the development of bispecific antibodies are meeting the requirement for upstream and downstream processes. Also, such a bispecific antibody should maintain the function and exhibit excellent biophysical properties such as solubility and stability that will not hinder the manufacturability of these molecules. Attempts have been made before to target two cytokines by bispecific antibody format to show dual targeting has better efficacy. Venkataramani et al developed and characterized a bivalent bispecific antibody scaffold termed Doppelmab. Doppelmabs have stronger affinity to the human targets compared to parental antibody formats (see for example, column 1 of page 20). The variable region sequences from humanized antibodies were formatted as IgG-like bivalent scaffold (Doppelmab, DM) (see for example, section 2.2 at column 2 of page 20). Both orientations (i.e. Vk-linker-VH and VH-linker-Vk) for the scFv modules in the Doppelmab scaffold to identify scFv's (single chain fragment variable) with optimal molecular attributes. All these clones were formatted as human IgG1 isotypes (see for example, section 2.2 at column 2 of page 20). Doppelmabs are symmetric IgG-like bispecifics that retain the canonical Fc domain like the traditional monoclonal antibodies. Often, the binding units are bi-valent for each antigen. There is an scFv fusion to the light chain of Fab and to the Fc domain (see for example, page 22 and figure 1). For Doppelmabs, irrespective of the capture format, strong affinity is shown by the antibodies to the targets (see for example, page 23).
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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