DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a pharmaceutical composition comprising a fusion protein comprising a targeting moiety and an immunomodulatory moiety; kits comprising the pharmaceutical composition; and methods of manufacturing the pharmaceutical composition in the reply filed on 16 February 2026 is acknowledged.
The Examiner notes that Group II claims 189, 193, and 196, have been voluntarily cancelled by the Applicant in response to the Restriction/Election requirement and as such cannot be withdrawn.
Applicant further elects the species of (i) a fusion proteins comprising the anti-EGFR domain VH CDRs 1-3 of SEQ ID NOs: 1, 2, and 3 respectively and VL CDRs 1-3 of SEQ ID NOs: 4, 5, and 6, respectively and the immunomodulatory domain of SEQ ID NO: 23 and (ii) a formulation of concentration of 50mg/ml; a buffer of 10mM citrate phosphate; a tonifying agent of 8% w/v sucrose; and a surfactant of 0.02% w/v polysorbate 80.
Response to Amendment
The amendment filed 16 February 2026 is acknowledged. Applicant has amended claims 162, 183, and 185. Claims 189, 193, and 196 are cancelled. Claims 197-199 are new.
Claim Status
Claims 162-188, 190-192, and 194-199 are pending and under examination in the instant office action.
Drawings
The drawings are objected to because: 1) The figure on p. 28/52 is mislabeled as "Fig. 52", which is a duplicate number; the specification refers to this figure as Fig. 28 [0092]; 2) Fig. 7 is missing x-axis labels. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 162-184, 186-188, 190-192, and 194-199 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 162, 165, 170, 175, 179, 180, 181, 186, 187, 191, and 194 recite the broad recitations "at least 95%"5-50 mg/ml” (claim 181), and the claims also recite a narrower version of each limitation (e.g. "at least 100%" (claim which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Written Description
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 162-184, 186-188, 190-192, and 194-199 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.
Regarding claim 162, 191, 95% identity to the TGFBR2 ECD allow for changes to the TGFB-contacting domain which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the function of binding TGFB.
Regarding claim 186, the claims is directed towards antibodies that bind to hEGFR comprising a heavy chain and light chain comprising 95% identity to SEQ ID NO: 10 and 11, which is the binding determinant region, but the art and genus of known species does not allow for predictable binding to the recited function of binding hEGFR.
Scope of the claimed genus
Claim 162 is directed at a pharmaceutical composition comprising a fusion protein comprising a targeting moiety and an immunomodulatory moiety wherein the targeting moiety specifically binds to hEGFR and the immunomodulatory moiety comprises the extracellular domain of human TGFβR II comprising an amino acid sequence at least 95% identical to SEQ ID NO: 23.
Claims 163-178, 181-182, and 197-199 are directed at limitations modifying the other components of the pharmaceutical composition and do not further limit the structure of the human TGFβR II ECD.
Claims 179, 180 are directed at functional limitations of the pharmaceutical composition that are not clearly linked to particular structures of the pharmaceutical composition or fusion protein.
Claims 183-184 limits the structure of the targeting moiety binding to hEGFR by reciting specific CDR sequences.
Regarding claim 186, 187, 191, and 194 the claims are directed towards TGFβR II ECD and the antibody that specifically binds hEGFR allowing for changes to the binding determinant region sequences as in claims 162 and 183.
Regarding claims 188, 192, and 195, the claims are directed towards method of manufacturing a pharmaceutical composition wherein the active steps of culturing the mammalian cells do not require the structures and the sequence and therefore does not limit the TGFβR II ECD of claim 162, 191, and 194 as described above.
Claim 185 is not included in this rejection because it recites that the immunomodulatory moiety comprises SEQ ID NO: 23.
State of the Relevant Art
Formation of an intact ligand-binding domain usually requires the folding of the complete structure of the ligand-binding portion of the extracellular domain of a receptor (e.g. Tang et. al., Machine learning on protein–protein interaction prediction: models, challenges and trends, Briefings in Bioinformatics, Volume 24, Issue 2, March 2023, bbad076, https://doi.org/10.1093/bib/bbad076). Although not prior art, Tang et. al. lays out the current advances and challenges of in silico prediction of protein-protein interactions (Abstract, Fig. 1, page 7 right column “Challenges in PPI prediction” section). Tang et. al. teaches that deep learning methods have been applied for the prediction of protein structure and have achieved high accuracy, but that 3D structural features have not been utilized and that further research on the usage of predicted structures to improve hybrid methods is required (page 8 right column ¶3). For example, Cosic et. al. teaches: “The most complex protein interactions are interactions between proteins and their receptors, which are proteins or complexes of proteins that selectively drive specific biological pathways. Currently, the selectivity of interactions between proteins and their receptors are investigated mostly using 3D matching between interacting proteins, which is not explicit enough to explain the high specificity of these interactions. Experimentally, protein–receptor interactions are investigated by a number of techniques including X-ray, MRI, spectroscopy, etc. However, all these techniques are very expensive and time consuming. Thus, there is a need for a biophysical approach that can investigate protein–receptor interactions with more specificity than 3D matching” (Cosic I, Paspaliaris V, Cosic D. Analysis of Protein–Receptor Interactions on an Example of Leptin–Leptin Receptor Interaction Using the Resonant Recognition Model. Applied Sciences. 2019; 9(23):5169. https://doi.org/10.3390/app9235169).
Regarding the TGFβR II ECD in particular, the structure of the wild-type human TGFβR II ECD has been solved and some of the TGFβ binding residues are known. Goebel et. al. teaches “TGFβ family ligands initiate signaling through the assembly of a receptor complex consisting of a ligand, two type I, and two type II receptors. Each receptor ECD consists of ∼100 residues exhibiting a three-finger toxin fold of three β-strands. Both type I and type II receptors display a high degree of homology, except for the extended loops that flank the core β-sheet. Four of the five type II and four of the seven type I receptor ECDs have been structurally characterized either alone (type II: ActRIIA, TBRII, BMPII/type I: Alk1, Alk3, Alk5) or in a ligand–receptor complex (type II: ActRIIA, ActRIIB, TBRII, BMPII/type I: Alk1, Alk3, Alk5, Alk6).3–13,16,20,24,28,36–42 These structures have revealed a common set of four disulfide bonds that stabilize the β-sheet structure in each receptor […] TβRII is unique in having two additional disulfide bonds to tether the β1–β2 loop in a position for ligand interaction” (Goebel, Erich J., et al. "Structural biology of the TGFβ family." Experimental Biology and Medicine 244.17 (2019): 1530-1546, p. 1532 right column ¶2). Goebel teaches that “TβRII is highly specific for binding to the TGFβ class (TGFβ1–3), while AMHRII is reserved exclusively for the ligand, antiMullerian hormone (AMH). While AMHRII has not been structurally characterized, the limited specificity of TβRII for the TGFβ class is well understood.10 During complex formation with TGFβ, TβRII binds at the distal fingertips of the ligand, where the receptor β-sheet is perpendicular to the β-strands of the fingers (Figure 1(d), center, orange). Specifically, β2 of TβRII forms significant contacts and binds within a cleft formed from positively charged residues (Arg303 and Arg372 in TGFβ1) – a feature shared by the TGFβ ligands.11 These residues account for TGFβ ligand specificity for TβRII and are not present in BMP or activin class ligands.47,48 This interaction is further stabilized by an extension in the β1–β2 loop that is limited to TβRII and AMHRII” (p. 1532 right column ¶4-p. 1533 left column ¶1). TGF-βRII ECD fusion proteins are also known in the art and are designed to “trap” TGF-β by binding ligand to non-signaling receptor. Zwaagstra, John C., et al. "Engineering and therapeutic application of single-chain bivalent TGF-β family traps." Molecular cancer therapeutics 11.7 (2012): 1477-1487 teaches that receptor-based ectodomain traps are a class of therapeutic agent that can be optimized using protein engineering approaches and that they previously increased the antagonist potency of the TβRII-ED by decreasing ligand dissociation rates. Zwaagstra et. al. teaches that covalent linkage of 2 receptor ectodomains in a single polypeptide rather than via dimerization domains (p. 1478, left column ¶2). Zwaagstra et. al. teaches that the trap slowed growth of a tumor by approximately 50% compared to saline controls, similar to a known antibody (Fig. 5).
Additionally, target TGFBRII ECD fusion proteins comprising a second targeting domain comprising an antibody are known in the art. For example, US20220017601 to Tian et. al. effectively filed 9 November 2019 (Of Record, IDS dated 2/29/2024) teaches a fusion protein comprising the TGFBRII ECD and an anti-PD-L1 antibody.
Regarding the anti-hEGFR binding domain, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) teaches the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further teaches antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu teaches the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Regarding anti-hEGFR antibodies, anti-EGFR antibodies are described in the art. For example, WO2021250275 to Dubey et. al. effectively filed 12 June 2020 teaches bispecific antibodies comprising anti-EGFR domains (p. 25 lines 6-10). Dubey et. al. teaches additional species of anti-EGFR bispecific antibodies, for example comprising SEQ ID NOs: 53, 54, 24, which comprises different CDRs to the instantly claimed SEQ ID NOs: 7 and 8. Thus, it would not be discernable a priori which residues of the CDRs are not required for binding and how they may be changed and still retain the anti-EGFR properties in the genus of antibodies with 95% sequence identity to SEQ ID NOs: 10 and 11.
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs or the ligand-binding domain of TGFβR II. And while it is possible to screen for variants that retain antigen binding or TGFβ binding, it is respectfully submitted that the number of possible substitutions permitted by “95% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 95% identity to SEQ ID NO: 23 allows for changes in any 6 amino acids and does not restrict the type or position of the amino acids to exclude those that determine ligand binding. 95% identity to SEQ ID NOs: 10 and 11 allow for change to 22 and 10 CDR residues of both the heavy and the light chain, respectively.
Summary of Species disclosed in the original specification
The instant specification discloses the exemplary hTGFβRII ECD domain of SEQ ID NO: 23 (Table 2, p. 47). The instant specification describes that the hTGFβRII ECD may be oriented by connecting to the C or N terminus of either the light or the heavy chain of the antibody [0225-0226].
Regarding EGFR binding variants, the instant specification discloses the anti-EGFR antibody cetuximab and panitumumab ([0187-0188]) and in particular the anti-EGFR antibody comprising HCDRs SEQ ID NOs: 1-3 and LCDRs SEQ ID NOs: 4-6, respectively [0197]; HCDRs SEQ ID NOs: 12-14 and LCDRs SEQ ID NOs: 15-17, respectively [0207]. The specification also discloses the exemplary anti-EGFR antibodies of Table 1 (p. 43).
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to allow substitution, addition, or deletion of any amino acid in SEQ ID NO: 23 of the described hTGFβRII ECD or the genus of anti-EGFR antibodies comprising any substitution, addition, or deletion of any amino acids (including CDR residues) in SEQ ID NOs: 10 and 11.
Do the disclosed species represent a genus?
MPEP §2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification describes a single species of hTGFβRII ECD and two species of anti-EGFR binding domain. A person of skill in the art would reasonably believe that the applicant was not in possession of the genus of any substitution, deletion, or addition up to 95% identity to SEQ ID NO: 23 and of the genus of anti-EGFR antibodies with any substitution, deletion, or addition to the CDRs of the disclosed anti-EGFR antibodies.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activities. The instant specification does not disclose any structure/function relationship between the hTGFβRII ECD and TGFβ binding, or provide any guidance or teaching on the structure/function relationship of which residues in SEQ ID NO: 23 may be changes. Additionally, the specification does not teach any structure/function relationship between the anti-EGFR CDR residues and anti-EGFR binding. As such, which residues in SEQ ID NOs: 23, 10, or 11 that retain the function of the immunomodulatory domain and the targeting domain would not be discernable a priori.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for the hTGFβRII ECD and antibody CDR residues for the recited function of binding TGFβ and EGFR, respectively. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 162 at the time of filing. Regarding claims 163-184, 186-188, 190-192, and 194-199 the claims are ultimately dependent on the rejected claim 162 without narrowing the claimed subject matter and thus are also rejected. The examiner notes that claim 185, which is limited to the composition comprising the immunomodulatory domain hTGFβRII ECD of SEQ ID NO: 23, is not subject to this rejection because it sufficiently narrows the claimed subject matter.
In order to obviate this rejection, the examiner recommends amending the claims to recite comprising SEQ ID NO: 23 as in claims 185, and to amend the dependent claims to require at least the binding determinant CDRs of the anti-hEGFR antibody as in dependent claim 183 without percent identity changes allowed in the anti-hEGFR CDRs.
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.
Claims 162-163, 165-188, 190, and 198-199 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 9988456 to Govindappa et. al. published 5 June 2018 (Of record, IDS dated 2/29/2024) in view of WO2020094122 to Tian et. al. published 14 May 2020 (citations refer to U.S. 20220017601A1 as equivalent English-language disclosure (Of record, IDS dated 2/29/2024)) and Kang, Jichao, X. Lin, and J. Penera. "Rapid formulation development for monoclonal antibodies." BioProcess Int 14.4 (2016): 40-47.
Regarding claims 162 and 177, Govindappa et. al. teaches a liquid pharmaceutical composition (Col. 17 lines 11-29) comprising a fusion protein that comprises a targeting moiety and an immunomodulatory moiety wherein the immunomodulatory moiety binds to TGF-β and the targeting moiety binds to EGFR (Col. 4 lines 26-32), wherein the immunomodulatory moiety comprises the amino acid sequence of the TGF-β extracellular domain (Col. 5 lines 12-20). Govindappa et. al. teaches that the TGF-β ECD comprises SEQ ID NO: 12 (Fig. 4) which is 100% identical to instant SEQ ID NO: 23 (reads on claims 162, 185). Govindappa et. al. teaches that pharmaceutically acceptable compositions refer to carriers, diluents, excipients and the like that can be administered to a subject and that various pharmaceutical formulations appropriate for administration to a subject are known in the art as described in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, Pa. (1990); and The Merck Index, 12th ed., Merck Publishing Group, Whitehouse, N.J. (1996) (Col. 17 lines 11-41). Govindappa et. al. teaches that the fusion Mabs were adjusted to neutral pH or stable formulation pH after purification (Col. 21 lines 64-Col. 22 line 2).
Regarding claims 183, 184, 185, 186, and 187, Govindappa et. al. teaches the fusion protein comprising SEQ ID NO: 28 and SEQ ID NO: 8 (Fig. 14), which are 100% identical to instant SEQ ID NO: 10 and SEQ ID NO: 29, comprising VH and VL CDRs 100% identical to instant CDRs of SEQ ID NOs: 1-3 and 4-6, respectively; comprising a VH and VL 100% identical to instant VH and VL SEQ ID NO: 7 and 8; comprising the TGFB-RII ECD 100% identical to instant SEQ ID NO: 23; and comprising targeting moiety heavy chain and light chain identical to instant SEQ ID NO: 10 and 11.
Regarding claim 188, Govindappa et. al. teaches a method of manufacturing the pharmaceutical composition comprising expressing a polynucleotide encoding the fusion polypeptide in a stable cell line such as a mammalian cell line (Col. 6 line 66-Col. 7 line 5); and additionally, a method a manufacturing comprising purifying the fusion protein from the cell supernatant and adjusting back to the stable formulation pH (Col. 21 line 48-Col. 22 line 2).
Govindappa et. al. does not teach the pharmaceutical composition comprising a buffer present at a concentration from 5 mM to 30 mM; a tonifying agent present at a concentration from 4%w/v to 10%w/v; and wherein the pharmaceutical composition has a pH from 5.5 to 7.0.
This deficiency is resolved by Tian et. al., Kang et. al., and
Tian et. al. teaches a pharmaceutical composition comprising a fusion protein comprising an immunomodulatory domain comprising the TGF-βRII ECD and a targeting domain comprising an anti-PD-L1 antibody, wherein the pharmaceutical composition comprises a buffer from 5mM to 30mM, preferably about 10mM [0022]; a saccharide, most preferably sucrose, from 50mg/mL to 100mg/mL (equivalent to 5% to 10% w/v) [0023-0025]; wherein the pH is from 5.0 to about 7.5, preferably 6.2 [0020] (reads on 6.0+0.3).
Regarding claim 163, Tian et. al. teaches the buffer is selected from a group consisting of a histidine salt buffer, a succinate buffer, a phosphate buffer, and a citrate buffer [0012].
Regarding claim 165-166, Tian et. al. teaches the buffer at a concentration from 5mM to 20mM, preferably 10mM [0022].
Regarding claims 167-169, Tian et. al. teaches the composition comprises a saccharide and the saccharide is trehalose or sucrose, most preferably sucrose [0023].
Regarding claim 198 and 170-171, Tian et. al. teaches the concentration of the saccharide is most preferably 80mg/mL (reads on 8% w/v) [0024].
Regarding claims 172-175 Tian et. al. teaches the composition comprises a surfactant, preferably polysorbate 80 [0026]. The surfactant is about 0.1mg/mL to 0.8mg/mL (equivalent to 0.01% to 0.08%) [0027].
Regarding claim 178, Tian et. al. teaches the composition may be lyophilized [0060-0064] (reads on powder).
Regarding claims 179-180, Tian et. al. teaches that a stable formulation of the antibody is a preparation wherein no changes are observed when stored at 2-8°C for preferably up to 1 year [0096] and testing for stability under conditions such as 5 cycles of freezing and thawing [0216].
Regarding claim 181 and 182, Tian et. al. teaches the concentration of the fusion protein from about 30 mg/mL to about 70mg/mL [0031] and in particular about 50mg/mL [0033].
Regarding claim 190, Tian et. al. teaches a kit comprising the pharmaceutical composition. Tian et. does not teach the kit comprises instructions for use; as stated in MPEP §2112.01 "Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability….[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate."
Kang teaches by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang teaches although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang teaches lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang teaches 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang teaches Table 1 lists excipients used in these antibody formulations. Kang teaches some commonalities can be observed: phosphate is present in 33% of formulations (page 40, middle column, second bullet) and 35% of liquid formulation (Table 1, page 42), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), and 72% of formulations used polysorbate 80 as a surfactant (page 40, middle column, third bullet). Kang teaches formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang teaches in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to take the pharmaceutical composition for stability of fusion proteins comprising a targeting moiety and the TGF-BRII ECD and optimize it for the fusion protein comprising an anti-EGFR antibody and the TGF-BRII ECD as taught by Govindappa et. al. in order to get a stable formulation as taught by Govindappa and in the method of obtaining a stable antibody formulation as taught by Kang et. al. This would result in a pharmaceutical composition comprising a fusion protein comprising SEQ ID NOs: 8 and 29 as taught by Govindappa comprising about 10mM citrate buffer as taught by Tian et. al.; comprising about 80mg/mL sucrose (reads on 8%w/v) as taught by Tian et. al.; and a polysorbate 80 concentration of from 0.1mg/mL to 0.8mg/mL (reads on 0.01% to 0.08% w/v), which overlaps with the instant 0.02% concentration (reads on claims 176 and 199), at a pH of 6.2 (reads on 6.0+0.3). This would further result in the stability characteristics as recited in claims 179-180 because both Kang et. al. and Tian et. al. teach optimizing for these stability characteristics and that the buffers, tonifying agents, and surfactants are results-effective variables to increase the stability of the fusion protein; using the same compositions in the same ranges for the same fusion protein would naturally result in the same stability characteristics. There is a reasonable expectation of success because:
The fusion protein of Govindappa et. al. has 100% sequence identity to the fusion protein of the instant application; and the fusion protein of Tian et. al. comprises an IgG targeting moiety that comprises an antibody (and would have highly similar structures as taught by Kang) and a TGF-BRII ECD 100% identical to the instant SEQ ID NO: 23. Govindappa et. al. recognized that antibody formulations comprising acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and known to those skilled in the art. Thus, utilizing known pharmaceutical reagents to produce stable formulations of known antibodies would be optimized for a highly similar fusion protein with the formulations of Tian et. al. and the results would affect the formulation with an expected range;
Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang taught it is common for commercial antibodies to have a formulation with citrate or phosphate, sucrose, and a surfactant as polysorbate 80 and that citrate has a pKa of 6;
Tian et. al. teaches that a highly similar fusion protein was stable in a formulation of citrate, sucrose, polysorbate 80, at a pH of 6.2.
Regarding claim 188, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of manufacturing comprising expressing the fusion protein stably in mammalian cells as taught by Govindappa and purifying it from the cell supernatant followed by adjustment back to the stable formulation as taught by Govindappa et. al. in the formulation buffer for increased stability as taught by Govindappa et. al. in view of Tian et. al. and Kang et. al. as described above. This would have a predictable effect because a person of ordinary skill in the art would expect to be able to use the general purification protocol and to reconstitute in the formulation buffer that was optimized as generically taught by Govindappa et. al.
Claim(s) 164, 191-192, and 194-197 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 9988456 to Govindappa et. al. published 5 June 2018 (Of record, IDS dated 2/29/2024) in view of WO2020094122 to Tian et. al. published 14 May 2020 (citations refer to U.S. 20220017601 A1 as an equivalent English-language disclosure (Of record, IDS dated 2/29/2024)) Kang, Jichao, X. Lin, and J. Penera. "Rapid formulation development for monoclonal antibodies." BioProcess Int 14.4 (2016): 40-47 as applied to claims 162, above, and further in view of WO2021250275 to Dubey et. al. effectively filed 12 June 2020.
The teachings of Govindappa et. al. in view of Tian et. al. and Kang et. al. are in the 103 above and are incorporated by reference herein. As described in the 103 above, Govindappa et. al. in view of Tian and Kang makes obvious a pharmaceutical composition comprising a fusion protein comprising an immunomodulatory domain and a targeting domain comprising SEQ ID NOs: 8 and 28 (100% identical to instant SEQ ID NOs: 10 and 29 and further comprising instant SEQ ID NOs: 11, 23, and 24); comprising 10mM citrate buffer, 80mg/mL sucrose (reads on 8%w/v sucrose); and polysorbate 80 at a concentration of 0.1-0.8mg/mL polysorbate 80 (reading on 0.01-0.08% w/v); wherein the pH of the composition in 6.2 (reads on 6.0+0.3).
Govindappa in view of Tian and Kang does not teach that the buffer is citrate-phosphate buffer.
This deficiency is resolved by Dubey et. al.
Dubey et. al. teaches diluent for diluting a drug product which comprises a hetero-dimeric multispecific immunoglobulin (Abstract). Dubey et. al. teaches that the heterodimeric antibody comprises an anti-EGFR targeting domain, wherein the anti-EGFR targeting domain may comprise the amino acid sequences of SEQ ID NOs: 45 and 46 (which comprise a VH and VL 100% identical to instant SEQ ID NOs: 7 and 8) (p. 25 lines 6-10); wherein the buffer is citrate-phosphate at a pH between 6.0 and 7.0 (See Example 2, p. 35). The citrate-phosphate buffer at pH 6 (Buffer C16) was found to be stable when stored at 5°C for 3 months (p. 52-53). Dubey et. al. teaches that usage of the dual-buffer system citrate-phosphate “dramatically improved the stability of diluents containing Lysine HCl as a stress storage condition”. C16 as a diluent was stable for up to 29 months when stored at 5°C (p. 59-61).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the citrate-phosphate buffer on Dubey et. al. for the citrate buffer of modified Govindappa et. al. in view of Tian et. al. and Kang et. al. in order to benefit from the long-term stability of a heterodimeric antibody comprising the same anti-EGFR VH and VL sequences in both Dubey et. al. and Govindappa et. al; and to further optimize the concentrations of the citrate-phosphate buffer of Dubey et. al. in the disclosed range of buffer concentrations as taught by Tian et. al. to arrive at 10mM citrate-phosphate buffer. This would have a reasonable expectation of success because Govindappa et. al. in view of Tian et. al. and Kang et. al. teaches that a person of ordinary skill in the art can determine the best formulations for stability and Dubey et. al. teaches a composition that is favorable for a similar multispecific protein as Govindappa et. al.; further, a person of ordinary skill in the art would expect to be able to substitute a dual buffer citrate-phosphate buffer system for the citrate buffer as taught by Tian et. al. and Kang et. al. teaches that phosphate is in 33% of formulations.
Conclusions
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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