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 37-38, 40, 44-45, 47-50, 62, 71-72, 107, 110-111, 122, 124 and 125 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/273,177, filed December 30, 2015, is acknowledged.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, 62/273,177, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The previously-filed 62/273,177 application does not disclose a method for preparing any conjugated protein, wherein the protein is any antibody or any antibody protein fusion as set forth in claims 107, 110-111, 124 and 125. The invention of claims 37-38, 40, 44-45, 47-50, 62, 71-72, 107, 110-111, 122, 124 and 125 was described in 15/394,500, now U.S. Patent 11,066,465.
Therefore for the purposes of applying prior art, the effective filing date of claims 107, 110-111, 124 and 125 is December 29, 2016, the date that the application 15/394,500 was filed. The invention of claims 37-38, 40, 44-45, 47-50, 62, 71-72 and 122 was described in application 62/273,177. Therefore the effective filing date of claims 37-38, 40, 44-45, 47-50, 62, 71-72 and 122 is December 30, 2015, the date that the provisional application 62/273,177 was filed.
Should applicant disagree with the examiner’s factual determination above, applicant should point to evidence that shows that the invention of claims 37-38, 40, 44-45, 47-50, 62, 71-72, 107, 110-111, 122, 124 and 125 is in fact described in one or more of the previously-filed applications.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 14, 2026 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Objection and Rejection Withdrawn
The objection to claim 37 is withdrawn as the claim has been canceled.
The written description rejection of claims 37-38, 40, 44-45, 47-50, 62, 71-72 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in light of the claim amendment.
The rejection of claims 37, 38, 48 under 35 U.S.C. 102 (a)(1) as being anticipated by Charles et al (of record, US20130045522, published Feb 7, 2013; PTO 1449) is withdrawn in view amendment to claim 37.
The rejection of claims 47, 57, 62, 71, 72 and 122 under 35 U.S.C. 103 as being unpatentable over Charles et al (of record, US20130045522, published Feb 7, 2013; PTO 1449) in view of the WO2013/093809 publication (of record, published June 27, 2013; PTO 892), US Pat No. 6,979,556 (of Record, issued Dec 27, 2005; PTO 892) and US patent 8,003,097 (of record, issued Aug 23, 2011; PTO 892) as applied to claims 37, 40, 44, 45 and 48 mentioned above and further in view of Perlroth (of record, US Patent No. 20150376271, claimed earliest priority to US 62018579, filed June 28, 2014; PTO 892) is withdrawn in view of the Perlroth does not qualify as prior art pursuant to 35 U.S.C. § 102(b)(2)(C).
The rejection of claims 107-109 under 35 U.S.C. 103 as being unpatentable over Junutula (of record, US20080311134, published December 18, 2008; PTO 892) in view of Charles et al (of record, US20130045522, published Feb 7, 2013; PTO 1449) is withdrawn in view of claim amendment.
The rejection of claims 110-111 under 35 U.S.C. 103 as being unpatentable over Junutula (of record, US20080311134, published December 18, 2008; PTO 892) in view of Charles I (of record, US20130045522, published Feb 7, 2013; PTO 892) as applied to claims 107-109 mentioned above and further in view of Charles II (of record, US 20130034517, published Feb 7, 2013; PTO 1449) is withdrawn in view of claim amendment.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 107, 110-111, 124 and 125 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that 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, 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.
Claim 107 encompasses a process for preparing a conjugated protein, the process comprising:
(a) reducing one or more cysteines in a protein to form a decapped protein in a solution, wherein the protein comprises at least one disulfide linkage and an engineered cysteine residue, wherein the protein is an antibody or any antibody protein fusion;
(b) reoxidizing the decapped protein to restore the at least one disulfide linkage in the reduced protein while ensuring that the engineered cysteine residue in the protein remains in a free thiol form to thereby form a reoxidized decapped protein in the solution;
(c) after (b), adding at least one excipient to the solution, wherein the excipient reduces a polymer induced protein precipitation;
(d) after (c), adding a polymer to the solution under conditions sufficient to conjugate the polymer to the reoxidized decapped protein at the engineered cysteine residue to form a conjugated protein, wherein the polymer is composed of MPC units and has a molecular weight between about 300,000 and 1,750,000 Da, and wherein the polymer comprises a terminal maleimide; and conjugating the polymer to the reoxidized decapped protein at the engineered cysteine residue to form a conjugated protein.
110. (Previously Presented) The process of claim 107, wherein the excipient is selected from the group consisting of at least one of: a detergent, a sugar, and a charged amino acid.
111. (Original) The process of claim 107, wherein reaction of a polymer with the reduced protein occurs under aqueous conditions between pH 6.0 to pH 8.5.
122. (Previously Presented) The method according to claim 49, wherein the polymer has 9 arms.
124. (New) The process of claim 107, further comprising contacting the solution comprising the conjugated protein to an ion exchange medium or hydrophobic interaction chromatography or affinity chromatography medium to separate the conjugated protein from the free polymer and from the reoxidized decapped protein.
125. (New) The process of claim 107, wherein the polymer comprises a PEG linker bridging a center of a polymer branching point to the terminal maleimide.
The specification exemplifies Protein Sequence of Antibody (0G1950) Comprising an Anti-VEGF-A Antibody Heavy Chain with an L443C (EU Numbering, or 449C in SEQ ID NO: 1) Mutation and an Anti-VEGFA-Antibody Light Chain.
[0381] An anti-VEGF-A antibody with an L443C (EU numbering) mutation having the sequence set forth below in SEQ ID NO. 1 (FIG. 12) (heavy chain) was cloned. An anti-VEGF-A antibody light chain having the sequence set forth in SEQ ID NO. 2 (FIG. 13) below was cloned.
Example 8a. Purification and Decapping of OG1950
[0382] The OG1950 heavy and light chains may be cloned into expression plasmids and transfected into CHO cells. Cells can be grown up in appropriate media and harvested. OG1950 may be purified using techniques described above. The OG1950 cysteine at position 443 (L443C (EU numbering)) residue is typically “capped” or oxidized by chemicals in the cell culture media and is not available for conjugation. In this regard, purified OG1950 may be subjected to a decapping (i.e. reducing) procedure to remove the cap and enable the free (i.e. those not involved in Cys-Cys disulfide bonds) cysteine residue to be conjugated to the maleimide functionality of a polymer. Decapping may be done by mixing purified OG1950 protein with a 30× molar excess for 1 hour at 25° C. of the reducing agent TCEP (3,3′,3″-Phosphanetriyltripropanoic acid). The reduction reaction with TCEP may be monitored by SDS-PAGE. Following denaturation, the OG1950 protein maybe washed by UFdF using a Pellion XL Ultrafiltration Cassette with 20 mM Tris pH7.5, 150 mM NaCl, 0.5 mM TCEP buffer to remove the cap. The TCEP reagent may then be removed in the same UFdF setup with 20 mM Tris pH7.5, 150 mM NaCl. Reduced OG1950 may then be allowed to refold using air (ambient oxygen) which again is followed by SDS-PAGE as an assay
Example 8b. Purification and Decapping of OG1950
[0383] The OG1950 heavy and light chains may be cloned into expression plasmids and transfected into CHO cells. Cells can be grown up in appropriate media and harvested. OG1950 may be purified using techniques described above. The OG1950 cysteine at position 443 (L443C (EU numbering)) residue is typically “capped” or oxidized by chemicals in the cell culture media and is not available for conjugation. In this regard, purified OG1950 may be subjected to a decapping (i.e. reducing) procedure to remove the cap and enable the free (i.e. those not involved in Cys-Cys disulfide bonds) cysteine residue to be conjugated to the maleimide functionality of a polymer. Decapping may be done by mixing purified OG1950 protein with a 30× molar excess for 1 hour at 25° C. of the reducing agent TCEP (3,3′,3″-Phosphanetriyltripropanoic acid). The reduction reaction with TCEP may be monitored by SDS-PAGE. Following reduction, the OG1950 protein can be washed by Ultrafiltration/Diafiltration (UF/DF) system using a Pellicon XL Ultrafiltration Cassette with 30 kDa MWCO membrane from Millipore with 20 mM Tris pH 7.5, 150 mM NaCl, 0.5 mM TCEP buffer to remove the cap and the excess TCEP. The residual TCEP reagent may then be removed in the same UF/DF setup with 20 mM Tris pH7.5, 150 mM NaCl. Reduced OG1950 can then be allowed to reoxidize using dHAA at ambient temperature for 1 hour followed by UF/DF for removal of dHAA to form decapped OG1950. The decapping status is monitored by SDS-PAGE assay.
Example 9. Conjugation of OG1950 to MPC Polymer
[0384] Decapped OG1950 may be conjugated to polymer OG1802. An excess of OG1802 is used (10-20 fold molar excess). Conjugation can be monitored by SDS-PAGE and driven to near completion. OG1950 conjugate may be purified via cation exchanger chromatography and buffer exchanged into the formulation buffer by UF/DF. Polymer-OG1950 conjugate may be purified chromatographically as described above.
Example 10. 0G1950 SPR Binding Kinetics
[0385] This Example illustrates binding of OG1950 to VEGF-165 in single cycle kinetics BIAcore™ experiment
[0386] SPR interaction analysis of OG1950 to human VEGF-165 was performed on a BIAcore™ T200 system (GE Healthcare) equipped with a protein A chip (GE Healthcare). A single-cycle kinetics method was implemented. Antibody was captured at 25 pg/mL in HBS-EP.sup.+ buffer (0.01 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 0.15 M sodium chloride, and 0.05% polysorbate 20) with a pulse of 25 s at a flow rate of 10 μl/min. Subsequently, recombinant human VEGF-165 (R&D Systems) was applied at various concentrations with a pulse of 60 s at a flow rate of 30 μl/min and a final dissociation time of 1000 s. The experiment was carried out at 25° C. The surface was regenerated with 10 mM glycine pH 1.7 for 1 min at a flow rate of 50 μl/min. Binding kinetics analysis was performed using the Biacore T200 evaluation software with responses globally fit to a 1:1 interaction. Results are summarized in Table 10.1 and FIG. 21.
Example 11—Conjugation and Purification of OG1953 Using Cation Exchanger Chromatography
[0387] OG1950 protein expression and protein preparation: OG1950 protein was expressed in mammalian GSCHOK1 expression system followed by purification using a Protein A affinity column. The purity of the Protein A column purified OG1950 was over 90% based on size exclusion chromatography and SDS-PAGE. The engineered specific cysteine residue of OG1950 was available for thiol conjugation to the OG1802 biopolymer. The thiol reacting chemical group of OG1802 was to react to form stable covalent linkage, which forms the OG1953 bioconjugate. To accomplish this, 1 mg of OG1950 was fully reduced with Tris-(2-Carboxyethyl)phosphine, Hydrochloride (TCEP) reducing agent followed by removal of TCEP via buffer exchange using a 30 KDa spin concentrator. The fully reduced OG1950 protein was then allowed to reoxidize to ensure all expected protein disulfide linkage was formed except the engineered cysteine residue (decap OG1950), which remained in reduced form for conjugation to the biopolymer via thiol specific conjugation chemistry.
Regarding antibody protein fusion (claim 107), there is not a single antibody fusion protein in the specification as filed.
Regarding the number of species of antibody, the specification discloses just one anti-VEGF-A antibody comprising a heavy chain and a light chain wherein the heavy chain is SEQ ID NO: 1 and wherein the light chai is SEQ ID NO: 2 wherein the anti-VEGF antibody heavy chain has a Q347C or substituted L443C (EU numbering or 449 in SEQ ID NO: 1, see para. [0219]). The anti-VEGF antibody (aka OG1950) comprises a sulfhydryl group is conjugated to the maleimide on the polymer comprising phosphorylcholine, see Examples 7, 10.
However, one species of anti-VEGF-A is not representative of the genus of antibody encompassed by the claimed method. The specification does not describe the complete structure, i.e., heavy and light chain variable regions or partial structure, i.e., the six CDRs of a sufficient number of species of the genus of antibody having any one or more engineered cysteine residues or the common structure share by members of the genus of antibodies, to reasonably convey to the skilled artisan that Applicant had possession of the claimed invention before the effective filling date of the claimed invention.
One of skill in the art was aware that the number and sequence of antibodies that bind to a single protein is a very large and structurally diverse genus (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes), as is evidenced below.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. of record, Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Furthermore, antibody that binds to tumor antigen from one species may not bind to the same antigen from another species.
For example, Yu et al (of record, Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 1449) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular). Thus, binding specificity associated with the particular heavy and light chain variable domains of the anti-VEGF-A antibody determines its use and method of making the same.
Thus, one of skill in the art cannot "visualize or recognize" most members of the genus of antibody or antibody fusion protein that correlated with function.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all 11-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. While Abbvie states that one does not need to disclose every species in a genus in order to meet the written description requirement, the specification must at least describe some species representative of the entire genus (see p. 25 of Abbvie).
Regarding adding any excipient to reduces any polymer induced any protein precipitation, the specification discloses:
Example 17 Excipients Screening Experiment for Prevention of OG1802 Polymer Induced IgG1 Precipitation
[0403] Using the standard conjugation reaction process setup, the OG1950 conjugation reaction mixture was found to be cloudy with precipitate immediately present upon mixing. Further investigation revealed the precipitate was the protein itself, which in turn resulted in poor conjugation efficiency observed via either SDS-PAGE or ion exchanger analysis as the protein was lost by precipitation instead of participating in the conjugation reaction.
[0404] Initial troubleshooting experiments performed revealed conditions that did not result in a clear reaction solution included (1) reduction of polymer molar excess ratio from over 10 to less than 5; (2) preadjusting the reaction solution pH to more acidic (e.g. pH 5) or basic (e.g. pH 8.5) from the standard neutral pH range (e.g. pH 6.5-7.5); (3) testing of other IgG1 protein samples with similar or different isoelectric point (pI) as compared to OG1950; (4) buffer exchanged the sample storage buffer into 1×PBS pH 7.4 or 20 mM Tris buffer pH 7.4, 100 mM NaCl; and (5) preadjusting the OG1802 solution with 20 mM Tris buffer pH 7.4.
[0405] Protein is known to carry net surface charge that helps protein solubility in aqueous solution. The amino acids are referred to as hydrophilic amino acids which include arginine, lysine, aspartic acid, and glutamic acid. At neutral pH 7 the side chains of these amino acids carry charges—positive for arginine and lysine, negative for aspartic acid, and glutamic acid. Altering the solution pH could modulate the intrinsic protein solubility which is therefore in some of the troubleshoot experiments mentioned above such as (2) this approach was applied. In theory, proteins solubility in aqueous solution differs depending on the level of hydrophobic or hydrophilic properties of the surface. Proteins with surfaces that have greater hydrophobic properties will readily precipitate. The addition of ions (e.g. NaCl or other salt) creates an electron shielding effect that nullifies some activity between water particles and the protein, reducing solubility as the proteins bind with each other and begin to aggregate. In the current situation, it was hypothesized that the biopolymer directly or indirectly modulates the protein surface charge and/or exposed surfaces in a manner that promotes the intermolecular hydrophobic interactions which results in protein precipitation.
[0406] Excipients that were determined to modulate protein solubility include the following categories (i) detergents including neutral detergent (e.g. 0.1-1% polysorbate20 or tween20) or charged detergent (e.g. 0.1-1% Sodium Dodecyl Sulfate (SDS)) (ii) sugars (e.g. 6% Trehalose or 6% sucrose) (iii) negatively charged amino acids (e.g. 0.03-1 mM glutamic acid or 0.03-1 mM aspartic acid) or positively charged amino acids (e.g. 1-100 mM lysine or arginine) (iv) chaotropic agents or denaturants (e.g. 1-100 mM urea, guanidine hydrochloride analog or 1-100 mM arginine) (v) polyethylene glycol (e.g. 0.03-1 mM PEG8000); and (vi) organic solvent (e.g. 20% ethanol).
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However, one species of OG1802 Polymer Induced just anti-VEGF IgG1 Precipitation by adding Tween 20, SDS, sucrose, Trehalose, aspartic acid, glutamic acid or arginine in Tris 20 mM at pH 7.4 is not representative of excipient, e.g., any detergent, any sugar, any charged amino acid and at pH between 6.0 to 8.5 for reducing all polymers induced any possible protein or antibody fusion protein precipitation.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010). AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014).
In Amgen Inc, v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc, v. Eli Lily & Co.. 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products - "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech. Ill USPQ2d 1780, 1790 (Fed. Cir. 2014).
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.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, it appears that the instant specification does not adequately disclose the breadth of method for preparing any conjugated protein as set forth in claims 107, 110, 111, 124 and 125 to meet the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicants’ arguments filed January 14, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that First, with regard to Claim 37, the present disclosure teaches numerous non-limiting options for providing a non-native cysteine residue in the Fc region of an antibody, and sulfhydryl specific reacting groups. See, e.g., Specification at [0225]-[0226]. The present Application also discloses non-limiting examples of anti-VEGF antibodies, including the amino acid sequences of the CDRs as recited in amended Claim 37. See, e.g., Specification at [0186]-[0187], [0193]-[0196], [0252]-[0253]. The present Application discloses non-limiting examples of cysteine residues introduced into the Fc region of the anti-VEGF-A antibody, and further provides guidance for suitable options for introducing such non-native cysteines. See, e.g., id. at [0254]-[0255]. The polymer MW range, number of arms, and sulfhydryl chemistry are likewise expressly disclosed. See, e.g., id. at [0015], [0030], [0014], [0024], [0242]. The Specification also discloses that conjugation to a non-native cysteine in the Fc region can proceed using sulfhydryl-reactive chemistry. See, e.g., id. at [0024], [0241]-[0242], Example 11. The recited feature of "contacting the anti-VEGF-A antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-VEGF-A antibody in which all cysteine residues are reduced" is expressly taught (see [0031], [0237]-[0239]). In addition, the present Application discloses working examples showing that an anti-VEGF-A antibody having the amino acid sequences set forth in SEQ ID NOs: 1 and 2 was decapped (using a thiol reductant), partially reoxidized, and conjugated via maleimide chemistry to a ~750 kDa MPC polymer, then purified and functionally characterized. See, e.g., id. at Examples 11-16.
Moreover, the pending claims recite the six CDRs of the anti-VEGF-A antibody, and that the non-native cysteine residue is in the Fc region, as discussed above. The present Application also provides guidance for adding the cysteine residue in the antibody. See, e.g., Specification at [0254]. Thus, the present disclosure provides not only working examples showing embodiments of the claimed method of making an antibody conjugate including an anti-VEGF-A antibody having the recited structural features, but also guidance for providing the non-native cysteine residue in the Fc region.
Second, with regard to Claim 107, the claim does not recite any anti-VEGF-A antibody, or a function of the protein. Rather, the claim recites that the protein is an antibody or an antibody protein fusion. Thus, the Office Action's assertions regarding the alleged variability of the heavy and light chain variable domains or the six CDRs do not support a prima facie case of non- compliance with the written description requirement. Further, the present disclosure provides numerous non-limiting examples of antibodies and the relevant structural features thereof. See, e.g., Specification at [0095]-[0099]. In addition, the present Application discloses working examples showing that an antibody was decapped (using a thiol reductant), partially reoxidized, and conjugated via maleimide chemistry to a ~750 kDa MPC polymer, then purified and functionally characterized. See, e.g., id. at Examples 11-16. At least for these reasons, one of ordinary skill in the art would reasonably conclude that Applicant had possession of the method of amended Claim 107 at the time of filing.
Finally, compliance with the written description requirement does not strictly require any representative species at all, much less any particular number. See MPEP 2163(II)(3)(a). That is, the Office Action's allegation that the Application discloses "just one" example of an anti-VEGF- A antibody is insufficient to satisfy the Office's burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims. See MPEP 2163 (II)(A)(3)(a)(ii) ("there may be situations where one species adequately supports a genus") (citing Rasmussen, 650 F.2d at 1214, 211 USPQ at 326-27).
With regard to Claim 40, solely to expedite examination, the claim is amended to recite among other features that the one or more mutations relative to an IgG1 constant domain to modulate effector function is selected from E233P, L234V, L234A, L235A, G237A, A327G, A330S and P331S (EU numbering). Applicant submits that one of ordinary skill in the art, in view of the present disclosure, would reasonably conclude that the Applicant had possession of the claimed method, including an anti-VEGF-A antibody constant domain as recited. See, e.g., Specification at [0199].
At least for these reasons, one of ordinary skill in the art, in view of the present disclosure, can reasonably conclude that the Applicant had possession of the claimed subject matter at the time of filing. As such, withdrawal of this rejection is respectfully requested.
In response, the amendment to claim 37 is acknowledged.
The argument with respect to claims 37 and 40 is moot as the rejection to those claims have been withdrawn.
In response to the argument that partially reoxidized, and conjugated via maleimide chemistry to a ~750 kDa MPC polymer, then purified and functionally characterized. See, e.g., id. at Examples 11-16, it is noted that the polymer in claim 107 is not limited to about 750 kDa as argued.
The specification discloses just one anti-VEGF-A antibody comprising a heavy chain and a light chain wherein the heavy chain is SEQ ID NO: 1 and wherein the light chai is SEQ ID NO: 2 wherein the anti-VEGF antibody heavy chain has a Q347C or substituted L443C (EU numbering or 449 in SEQ ID NO: 1, see para. [0219]). The anti-VEGF antibody (aka OG1950) comprises a sulfhydryl group is conjugated to the maleimide on the polymer comprising phosphorylcholine, see Examples 7, 10.
However, one species of anti-VEGF-A antibody is not representative of the genus of antibody or antibody fusion protein encompassed by the claimed method. The specification does not describe the complete structure, i.e., heavy and light chain variable regions or partial structure, i.e., the six CDRs of a sufficient number of species of the genus of antibody having any one or more engineered cysteine residues or the common structure share by members of the genus of antibodies, to reasonably convey to the skilled artisan that Applicant had possession of the claimed invention before the effective filling date of the claimed invention.
Regarding antibody protein fusion (claim 107), there is not a single antibody fusion protein in the specification as filed.
Regarding adding any excipient after the reoxidizing step (b), the specification discloses Screening Experiment for Prevention of OG1802 Polymer Induced IgG1 Precipitation by adding (i) detergents including neutral detergent (e.g. 0.1-1% polysorbate20 or tween20) or charged detergent (e.g. 0.1-1% Sodium Dodecyl Sulfate (SDS)), (ii) sugars (e.g. 6% Trehalose or 6% sucrose) (iii) negatively charged amino acids (e.g. 0.03-1 mM glutamic acid or 0.03-1 mM aspartic acid) or positively charged amino acids (e.g. 1-100 mM lysine or arginine), (iv) chaotropic agents or denaturants (e.g. 1-100 mM urea, guanidine hydrochloride analog or 1-100 mM arginine) (v) polyethylene glycol (e.g. 0.03-1 mM PEG8000); and (vi) organic solvent (e.g. 20% ethanol). Only the particular excipients shown in Table 17.1 reduced polymer OG1802 Polymer Induced IgG1 Precipitation.
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However, various factors affecting protein precipitation or aggregation include optimal pH, hydrophobicity of the crosslinker, protein concentration, buffer, temperature, ionic strength, isoelectric point (pI) of different antibody and antibody fusion protein. Incorporating different surfactants (polysorbate 20), or sugars or specific amino acids into the reaction buffer may increase hydrophobicity of the protein after conjugation.
As such, it is submitted that a skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus of excipients, detergent, sugar, antibody and antibody fusion protein encompassed by the claimed method.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
For at least these reasons, one of ordinary skill in the art cannot visualize or recognize most members of the genus of antibody or antibody protein fusion and excipients encompass by the claimed method. Thus, one of one of ordinary skill in the art would reasonably conclude that the Applicant was not in possession of the claimed subject matter at the time of filing. As such, the rejection is maintained.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
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 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.
Claims 37, 40, 44, 45, 48-50 and 122 are rejected under 35 U.S.C. 103 as being unpatentable over Charles et al (of record, US20130045522, published Feb 7, 2013; PTO 1449) in view of the WO2013/093809 publication (of record, published June 27, 2013; PTO 892), US Pat No. US Pat No. 6,979,556 (of Record, issued Dec 27, 2005; PTO 892) and US patent 8,003,097 (of record, issued Aug 23, 2011; PTO 892).
Regarding claims 37, 48, Charles teaches a method of making antibody conjugate comprising linking or coupling any functional agents to phosphorylcholine containing polymer, see entire document, para. [0162] to [0164]. Examples of functional agent or therapeutic antibodies (or their respective scFv or Fab fragments) that may serve as bioactive agents include, but are not limited, to Bevacizumab (Genentech) is an anti-VEGF human monoclonal antibody; and Ranibizumab (Genentech) is a chimeric (mouse and human) monoclonal antibody used to treat macular degeneration, anti-VEGF scFv, see para. [0175], [0256]. The reference anti-VEGF scFv comprises a C-terminal (aka outside a variable region) cysteine, see para. [0256], may also comprise non-naturally occurring amino acids, e.g., replacement of a serine by cysteine (aka non-native cysteine, see para. [0180], [0182], [0256]. The reference biological agent is conjugate to a phosphorylcholine containing polymer comprising a sulfhydryl specific reacting group, e.g., maleimide, see para. [0252], [0257], Example 16.
Regarding claim 38, Charles teaches exemplary monoclonal the anti-VEGF antibody bevacizumab or rhuMAb-VEGF, which is an IgG1 antibody having Fc (see para. [0171], [0202]), and has a C-terminal cysteine for site-specific conjugation, see para. [0174].
Regarding claim 49, Charles teaches the phosphorylcholine containing polymer, e.g., 2-methacryloyloxyethyl phosphorylcholine (HEMA-PC) or 2-methacryloyl-2'-trimethylammonium ethyl phosphate (MPC) has a molecular weight of 350,000 to 1,250,000 Daltons, which is within the claimed range of 300,000 and 1,750,000, see para. [0006], [0040], [0096]. The reference 2-methacryloyl-2'-trimethylammonium ethyl phosphate (MPC) intrinsically has the claimed structure
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Regarding claim 50, Charles teaches that the polymer has 2, 3, 4, 5, 6, 7, 8 or more arms, see para. [0086]. Claim 122 is included as the reference teaches more than 8 arms, which include the claimed 9-arms.
Charles teaches that where a thiol is reacted with a maleimide to form a thioether bond, the reaction is typically carried out at a pH of 6.5 to 7.5, which is within claimed range of between pH 6.0 to pH 8.5. Excess maleimide groups can be quenched by adding free thiol reagents such as mercaptoethanol, see para. [0229].
Charles does not teach the anti-VEGF-A antibody comprises a light chain and a heavy chain, wherein the anti-VEGF-A antibody heavy chain comprises CDRH1: GYDFTHYGMN (SEQ ID NO: 9), CDRH2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDRH3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the anti- VEGF-A antibody light chain comprises CDRL1: SASQDISNYLN (SEQ ID NO: 12), CDRL2: FTSSLHS (SEQ ID NO: 13), and CDRL3: QQYSTVPWT (SEQ ID NO: 14) as per claim 37 and wherein the anti-VEGF-A antibody heavy chain isotype is IgG1 and comprises the mutations are (EU numbering) L234A, L235A, and G237A as per claim 44 and wherein the cysteine residue is added by recombinant DNA technology at Q347C (EU numbering) as per claim 45.
However, the WO2013/093809 publication teaches one or more mutations, e.g., cysteine engineered at position Q347C (see p. 138 Table 14) and L443C (See Table 11) in the Fc region of an antibody, numbering according to the EU index as per claim 45, see p. 98, first paragraph for efficiency of conjugation of various agent of interest to the antibody, see p. 98, in particular. The introduction of cysteines at various positions of human IgG1 did not affect antibody binding to cells, see p. 151, in particular. The WO2013/093809 publication teaches that the conjugation process is performed by contacting the non-native cysteine containing antibody with a thiol reductant, e.g., TCEP under conditions that produce a reduced cysteine sulfhydryl group, followed by re-oxidation of the internal disulfides with an oxidizing agent, e.g., DHA (dehydroascorbic acid), which allowed for a conjugation with maleimides as per claim 48 that resulted in a more homogenous ADC, see Example 8. The WO2013/093809 publication teaches that methods for conjugation another substance to an antibody are well known in the art, see p. 84-85, p. 90-94. The WO2013/093809 publication teaches PEG linker, e.g., PEG-C2, see p. 92-93. The cysteine engineered antibodies wherein a cysteine has been introduced present at least one sulfhydryl (-SH) group for conjugation, see p. 96, last paragraph, in particular. Example of engineered cysteine L443C (Kabat EU), p. 125. The conjugation method comprises contacting the cysteine engineered antibody with a thiol reductant, e.g., dithiothreitol (DTT), see p. 129, p. 145-146, Example 8. To improve homogeneity of loading, the method comprises complete reduction (aka all cysteine residues are reduced) of the engineered antibody with TCEP (tris2-carboxyethyl)phosphine) followed by re-oxidation of the internal disulfides with DHA (dehydroascorbic acid) was used which allowed for a conjugation with maleimides that resulted in a more homogenous ADC, see p. 146, second paragraph, Method B, in particular. After reoxidation, the material was buffer exchanged into 1 ml of PBS. Purification by SEC was performed as needed to remove any aggregated material, see p. 146.
Charles and the WO2013/093809 publication do not teach the anti-VEGF-A antibody comprises a light chain and a heavy chain, wherein the anti-VEGF-A antibody heavy chain comprises CDRH1: GYDFTHYGMN (SEQ ID NO: 9), CDRH2: WINTYTGEPTYAADFKR (SEQ ID NO: 10), and CDRH3: YPYYYGTSHWYFDV (SEQ ID NO: 11), and the anti- VEGF-A antibody light chain comprises CDRL1: SASQDISNYLN (SEQ ID NO: 12), CDRL2: FTSSLHS (SEQ ID NO: 13), and CDRL3: QQYSTVPWT (SEQ ID NO: 14) as per claim 37 and wherein the anti-VEGF-A antibody heavy chain isotype is IgG1 and comprises the mutations are (EU numbering) L234A, L235A, and G237A as per claim 44.
However, the ‘556 patent teaches full length IgG1 antibody that binds to VEGF-A wherein the antibody heavy chain comprising the claimed CDRH1 GYDFTHYGMN, CDRH2 WINTYTGEPTYAADKFR and CDRH3 YPYYYGTSHWYFDV, respectively, which are identical to instant SEQ ID NO: 9, 10 and 11, respectively, as per claim 39, see reference SEQ ID NO: 11 reproduced below:
US-10-020-786-11
Query Match 99.0%; Score 2425; DB 2; Length 476;
Best Local Similarity 99.1%;
Matches 449; Conservative 0; Mismatches 4; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 24 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTY 83
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 84 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVT 143
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 144 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 203
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 240
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 204 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL 263
Qy 241 AGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 300
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 264 LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 323
Qy 301 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 324 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 383
Qy 361 REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 384 REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 443
Qy 421 SRWQQGNVFSCSVMHEALHNHYTQKSLSCSPGK 453
|||||||||||||||||||||||||||| ||||
Db 444 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 476
The reference anti-VEGF-A antibody wherein the antibody light chain of SEQ ID NO: 10 comprises the claimed CDRL1 SASQDISNYLN (instant SEQ ID NO: 12), CDRL2 FTSSLHS (instant SEQ ID NO: 13) and CDRL3 QQYSTVPWT (instant SEQ ID NO: 14), respectively as per claim 39.
Query Match 100.0%; Score 1114; DB 5; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
The ‘556 patent further teaches the Fc region of the full length antibody may comprises amino acid modification such as cysteine residue(s) at one or more positions 297, 298, 299, 264, 265 and 239 (numbering according to the EU index as in Kabat). After expression, the cysteine substituted antibody variant can have various forms of PEG (or pre-synthesized carbohydrate) chemically linked to the free cysteine residues, see col. 28, lines 6-33, in particular. The reference anti-VEGFA antibody and conjugate thereof are useful for treating various diseases such as cancer, see col. 12, col. 32.
The ‘556 patent does not teach the anti-VEGF antibody further comprises at least one of the following mutations L234A, L235A, and G237A as per claim 44.
However, the ‘097 patent teaches mutations on adjacent or close sites in the hinge link region (e.g., replacing residues 234, 235, 236 and/or 237 with another residue) in all of the isotypes reduce affinity for Fc.gamma. receptors, particularly Fc.gamma.RI receptor. A preferred combination of mutants is L234A, L235A and G237A for human isotype IgG1 as per claims 40 and 44, see col. 43, lines 34-44, in particular.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to modify the anti-VEGF antibody conjugate of Charles in view of the WO2013/093809 publication, the ‘556 patent and the ‘097 patent by conjugating Charles’ phosphorylcholine containing polymer to WO2013/093809 publication or the ‘556 patent’s cysteine engineered anti-VEGF-A IgG1 antibody comprising a heavy chain variable region and a light chain variable region having the heavy and light chain CDRs as taught by the ‘556 patent wherein the Fc having a C-terminus Q347C and L443C substitution (away from the variable region of the antibody) for site-specific efficient conjugation as taught by WO2013/093809 publication and wherein the Fc including the L234A, L235A, and G237A substitution as taught the ‘097 patent in order to reduce affinity for Fc.gamma. receptors, particularly Fc.gamma.RI receptor with a reasonable expectation of success.
The person of ordinary skill would have had a reasonable expectation of success in site-specific conjugating phosphorylcholine containing polymer having a molecular weight of between 300,000 to 1,250,000 Daltons and maleimide group to the anti-VEGF-A antibody at Q347C or L443C having L234A, L235A and G237A substitution to reduce effector function using the process of the WO2013/093809 publication since Charles teaches the water soluble polymer has reduced immunogenicity, increased half-life, increased solubility and decreased clearance of the conjugate, see para. [0010] and the WO2013/093809 publication teaches that complete reduction (aka all cysteine residues are reduced) of the engineered antibody with TCEP (tris2-carboxyethyl)phosphine) followed by re-oxidation of the internal disulfides with DHA (dehydroascorbic acid) was used which allowed for a conjugation with maleimides that resulted in a more homogenous ADC, see p. 146, second paragraph, Method B, in particular. The conjugation of familiar elements according to known method is likely to be obvious when it does no more than yield predictable results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
One of ordinary skill in the art would have been motivated to substitute Q347 and/or L443 for cysteine residues Q347C and L443C in the Fc because the WO2013/093809 publication teaches introduction of cysteines at these positions in the Fc of human IgG1 did not affect antibody binding to cells (see p. 151, in particular) and Charles teaches conjugating anti-VEGF-A antibody to phosphorylcholine containing polymer reduces immunogenicity and increase half-life of the conjugate, see para. [0009], [0011]).
One of ordinary skill in the art would have been motivated to site-specific conjugating phosphorylcholine containing polymer to the anti-VEGF at Q347 or L443C away from the variable region because the WO2013/093809 publication teaches that introduction of cysteines at these positions in the Fc of human IgG1 (away from the antigen binding site) did not affect antibody binding to cells, see p. 151, in particular.
One of ordinary skill in the art would have been motivated to include L234A, L235A and G237A substitutions in the Fc of the anti-VEGF-A antibody because the ‘097 patent teaches replacing residues L234A, L235A and G237A in human isotype IgG1 would reduce affinity for Fc gamma receptors, thereby reducing effector function, see col. 43, lines 34-44, in particular.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Applicants’ arguments filed January 14, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that Claim 37 is amended, solely to expedite examination. Amended Claim 37 is non-obvious over the cited references at least because the asserted combination of the cited references fails to teach or suggest all elements of the claim. As amended, independent Claim 37 now recites "contacting the anti-VEGF-A antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-VEGF-A antibody in which all cysteine residues are reduced." This feature was previously recited in Claim 57, which was not included in this rejection as the asserted combination of the cited references fails to teach or suggest at least this feature. At least for this reason, a prim facie case of obviousness of the claimed methods has not been established over the asserted combination of the cited references. As such, Applicant respectfully requests withdrawal of this rejection.
In response, the amendment to claim 37 is acknowledged.
In response to the argument that "contacting the anti-VEGF-A antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-VEGF-A antibody in which all cysteine residues are reduced”, it is noted that WO2013/093809 publication teaches
methods for conjugation another substance to an antibody are well known in the art, see p. 84-85, p. 90-94. The WO2013/093809 publication teaches cysteine engineered antibodies wherein a cysteine has been introduced present at least one sulfhydryl (-SH) group for conjugation, see p. 96, last paragraph, in particular. Example of engineered cysteine L443C (Kabat EU), p. 125. The conjugation method encompasses contacting the cysteine engineered antibody with a thiol reductant, e.g., dithiothreitol (DTT), see p. 129, p. 145-146, Example 8. To improve homogeneity of loading, the method comprises complete reduction (aka all cysteine residues are reduced) of the engineered antibody with TCEP (tris2-carboxyethyl)phosphine) followed by re-oxidation of the internal disulfides with DHA (dehydroascorbic acid) was used which allowed for a conjugation with maleimides that resulted in a more homogenous ADC, see p. 146, second paragraph, Method B, in particular.
In fact, instant specification uses the same cysteine engineered anti-VEGF-A and reduction with the same TCEP and DHA, see Examples 7, 8a-8b.
For these reasons, the rejection is maintained.
Claims 49-50 stand rejected under 35 U.S.C. 103 as being unpatentable over Charles et al (of record, US20130045522, published Feb 7, 2013; PTO 1449) in view of the WO2013/093809 publication (of record, published June 27, 2013; PTO 892), US Pat No. 6,979,556 (of Record, issued Dec 27, 2005; PTO 892) and US patent 8,003,097 (of record, issued Aug 23, 2011; PTO 892) as applied to claims 37, 40, 44, 45 and 48 mentioned above and further in view of US2010/0166700 publication (of record, published July 1, 2010; PTO 892).
The combine teachings of Charles, the WO2013/093809 publication, the ‘556 patent and the ‘097 patent have been discussed supra.
The references above do not teach the antibody conjugate wherein the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2’-(trimethylammonium)ethyl phosphate (MPC) monomers as set forth in claim 49 wherein the polymer has 3-12 arms as set forth in claim 50.
However, the US2010/0166700 publication teaches and claims an antibody conjugate comprising phosphorylcholine containing polymer such as 2-methacryloyl-2'-trimethylammonium ethyl phosphate (aka MPC) as per claim 49, see para. [0143] having the structure as shown in [0384] covalently conjugated (see para [0114]) to an antibody such as bevacizumab that binds to VEGF-A (see para. [0104], [0294], reference claim 30, in particular).
Regarding claim 50, the US2010/0166700 publication teaches the polymer possess 2 or more arms, such as 3 polymer arms, 4 polymer arms, 5 polymer arms, 6 polymer arms, 8 polymer arms or more, see para. [0170].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to modify the antibody conjugate of Charles, the WO2013/093809 publication, the ‘556 patent and the ‘097 patent in view of the US2010/0166700 publication by substituting a known phosphorylcholine containing polymer in the conjugate for another, e.g., another phosphorylcholine containing polymer such as 2-methacryloyl-2'-trimethylammonium ethyl phosphate (MPC) having three or more arms and a molecular weight between about 0.5 kDa (aka 500 Da) and about 200 kDa (aka 200,000 Da) as taught by the US2010/0166700 publication with a reasonable expectation of success, i.e., an antibody conjugate comprising an anti-VEGF-A and phosphorylcholine containing polymer such as 2-methacryloyl-2'-trimethylammonium ethyl phosphate covalently bounded to the antibody at a non-native cysteine away from the variable region of the antibody.
One of skill in the art would have been motivated to do so because the US2010/0166700 publication teaches the large water soluble polymer has reduced immunogenicity and increased half-life, see para. [0004], less frequent dosing, see para. [0004], increased solubility and decreased clearance, see para. [0004].
The claims would have been obvious because the substitution of one known element (i.e.phosphorylcholine containing polymer for another (i.e. another phosphorylcholine containing polymer such as 2-methacryloyl-2'-trimethylammonium ethyl phosphate) would have yielded predictable results (i.e. increases molecular weight of the conjugate with multiple phosphorylcholine groups) to one ofordinary skill in the art at the time of the invention. In addition, the claims would have beenobvious because "a person of ordinary skill has good reason to pursue the known options withinhis or her technical grasp. If this leads to the anticipated success, it is likely the product not ofinnovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc.,82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Applicants’ arguments filed January 14, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that Claim 37 is amended, solely to expedite examination. Amended Claim 37 is non-obvious over the cited references at least because the asserted combination of the cited references fails to teach or suggest all elements of the claim. As amended, independent Claim 37 now recites "contacting the anti-VEGF-A antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-VEGF-A antibody in which all cysteine residues are reduced." As the US2010/0166700 publication was cited solely for allegedly disclosing that the phosphorylcholine-containing polymer comprises MPC monomers or has three or more arms, the asserted combination of references also fails to teach or suggest all elements of Claim 37 as amended. At least for this reason, a prima facie case of obviousness of Claim 37 as amended, as well as each claim dependent therefrom, has not been established over the asserted combination of the cited references. As such, Applicant respectfully requests withdrawal of this rejection.
In response, the amendment to claim 37 is acknowledged.
In response to the argument that "contacting the anti-VEGF-A antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-VEGF-A antibody in which all cysteine residues are reduced”, it is noted that WO2013/093809 publication teaches
methods for conjugation another substance to an antibody are well known in the art, see p. 84-85, p. 90-94. The WO2013/093809 publication teaches cysteine engineered antibodies wherein a cysteine has been introduced present at least one sulfhydryl (-SH) group for conjugation, see p. 96, last paragraph, in particular. Example of engineered cysteine L443C (Kabat EU), p. 125. The conjugation method encompasses contacting the cysteine engineered antibody with a thiol reductant, e.g., dithiothreitol (DTT), see p. 129, p. 145-146, Example 8. To improve homogeneity of loading, the method comprises complete reduction (aka all cysteine residues are reduced) of the engineered antibody with TCEP (tris2-carboxyethyl)phosphine) followed by re-oxidation of the internal disulfides with DHA (dehydroascorbic acid) was used which allowed for a conjugation with maleimides that resulted in a more homogenous ADC, see p. 146, second paragraph, Method B, in particular.
In fact, instant specification uses the same cysteine engineered anti-VEGF-A and reduction with the same TCEP and DHA, see Examples 7, 8a-8b.
For these reasons, the rejection is maintained.
Conclusion
Claims 47, 71 and 72 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641