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 .
Claim Status
Applicant’s amendments received 03SEP2025 are acknowledged.
Claims 19, 22, and 26 have been canceled.
Claims 20, 23, 25, 27-28, 30-36, 38-39, and 41-43 have been amended.
Claims 1-18, 20-21, 23-25, and 27-48 are pending in the instant application.
Claims 1-18 and 45-48 remain withdrawn.
Claims 1, 20, and 45-48 are currently independent.
Claims 20-21, 23-25, and 27-44 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/AU2020/050527, filed 27MAY2020, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of AU 2019901808 filed on 27MAY2019 has been received and is acknowledged.
Specification
Applicant’s arguments, see p 12, Objections to the specification section, filed 03SEP2025, with respect to objections to the specification for minor informalities and failing to comply with the sequence listing requirements have been fully considered and said objections to the specification have been withdrawn in view of amendments to the specification filed as part of said response.
Claim Objections
Applicant’s arguments, see p 12-13, Objection to the claims section, filed 03SEP2025, with respect to objections to claim(s) 19 and 23-44 (claims 19 and 26 have been cancelled) for informalities have been fully considered and said objections to claim(s) 23-25 and 27-44 have been withdrawn in view of claim amendments filed as part of said response.
Claim Rejections - 35 USC § 112
Indefiniteness
Applicant’s arguments, see p 13-14, 35 USC §112, second paragraph section filed 03SEP2025, with respect to the rejection(s) of claim(s) 21-44 (claims 22 and 26 have been cancelled) under 35 USC §112(b) have been fully considered and said rejections of claims 21, 23-25, and 27-44 have been withdrawn in view of the claim amendments filed as part of said response.
Dependency
Applicant’s arguments, see p 14-15, 35 USC §112, fourth paragraph section, filed 03SEP2025, with respect to the rejection(s) of claim(s) 28-44 under 35 USC §112(b) have been fully considered and said rejections of claims 28-44 have been withdrawn in view of the claim amendments filed as part of said response.
35 USC §112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Applicant’s arguments, see p 15-17, 35 USC §112, first paragraph section, filed 03SEP2025, with respect to the rejection(s) of claim(s) 19, 22-25, 27-37, and 38-44 (claims 19 and 22 have been cancelled) under 35 USC §112(a) – written description have been fully considered and said rejections of claims 23-25, 27-37, and 38-44 have been withdrawn in view of the claim amendments filed as part of said response.
Applicant’s claim amendments received as part of the 03SEP2025 response have necessitated the following new grounds of rejection.
Claims 20-21, 23-25, 27-37, and 39-44 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.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of a reagent (such as the epitope to which the reagent binds or the fact that it does or does not inhibit some process) does not provide evidence of possession of the reagent itself.
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), the following is noted. To show invention, a patentee must convey in its disclosure that they “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). Further, 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). Indeed, the courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69. It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”. Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
Applicant has broadly claimed a method of treating or preventing an inflammatory neurological disease in a subject, the method comprising administering to a subject a (binding) protein comprising an extracellular domain of CD39 and a binding region that specifically binds to activated GP IIb/IIIa, wherein the binding region specifically binds an epitope on GPIIb/IIIa recognized by a scFv consisting of a sequence set forth in SEQ ID NO: 1 (i.e., claims 20 and 21). The broadest claims do not require fusion protein to have any function apart from hydrolyzing ATP and ADP into AMP (i.e., CD39 extracellular domain) and binding GPIIb/IIIa at the same epitope as the scFv of SEQ ID NO: 1 (i.e., binding region), with dependent limitations adding additional functional limitations, such as, binding GPIIb/IIIa and neutralizing GPIIb/IIIa receptors (i.e., claim 27) or decrease in plasma levels of ADP, etc. (i.e., claim 42). No claims recite any specific or particular structure of the fusion protein that necessarily gives rise to the specific treatment functions upon administration to a subject, apart from claim 38, which is limited to a specific structure of the fusion protein. Furthermore, claims 23-25, 27-37, and 39-44 are also rejected since they depend from claim 20, but do not remedy this deficiency. Examiner notes that partial structures are recited in claims 25, 31-37, and 39-40, dependent on claim 21 which is dependent on claim 20; however the specification does not provide sufficient written description for the specific structure of the binding region to function to bind to the same epitope as the scFv consisting of the amino acid of SEQ ID NO: 1. Specifically, in the instance of claims 31-34, the claims encompass binding protein structures (i.e., scFvs or VH/VL pairs) comprising a sequence that is 90% identical to specific SEQ ID NOs (i.e., binding proteins with potential CDR mutations), but neither the claims nor the specification define where the mutation can occur that will maintain the claimed specificity.
To support such broad claims, the specification teaches the involvement of platelets and their role in inflammation as related to multiple sclerosis (MS) and the use of a recombinant fusion protein, comprising the extracellular domain of CD39 and a targeting protein binding activated GPIIb/IIIa for improved treatment of inflammatory neurological disease (see p 2-3). The specification hypothesizes that the binding protein component of the fusion protein targets and inhibits (i.e., neutralizes) natural ligand (i.e., fibrinogen/fibrin) binding to activated GPIIb/IIIa on activated platelets and the CD39 (i.e., an anti-platelet factor) component of the fusion protein enriches CD39, which together enriches CD39 to activated platelets (p 3, lines 4-6, p 24, lines 4-7). Furthermore, CD39 is also known as ectonucleoside triphosphate diphosphohydrolase-1, and is an enzyme on the cell surface, with the catalytic site facing extracellularly and GPIIb/IIIa is also known as integrin αIIbß3 and is an integrin complex found on platelets, which is formed via calcium-dependent association of GPIIb and GPIIIa and is involved in platelet activation and aggregation by binding to fibrinogen (p 22, lines 9-36). The binding protein portion comprises an antibody variable region that binds to GPIIb/IIIa, or the variable region fragment (Fv), selected from a group of: (i) a single chain fragment (scFv), (ii) dimeric scFv (di-scFv),…or (xi) an antibody (p 3, line 35 to p 4, line 13). Additionally, the fusion protein further comprises human serum albumin (i.e., HSA) resulting in the structures: HSA-scFv-CD39, scFv-HSA-CD39, or scFv-CD39-HSA (p 10, lines 5-16). Furthermore, the specification teaches treatment and prevention of inflammatory neurological disease includes administering a protein described within the specification to thereby reduce or eliminate at least one symptom or administering a protein described within the specification to thereby stop or hinder the development of at least one symptom or hinder relapse of any disorder characterized by a defect in neuronal signaling and/or neuronal dysfunction and/or neuronal cell death resulting from an inflammatory and, in some examples, an autoimmune response (p 28, lines 11-20 and p 23, lines 1-4). Additionally, exemplary inflammatory neurological diseases include multiple sclerosis, systemic lupus erythematosus (SLE), Guillain-Barre syndrome, Lamber-Eaton myasthenic syndrome, myasthenia gravis, transverse myelitis, leukodystrophy, and progressive multifocal leukoencephalopathy (p 34, lines 24-27). A key to the sequence listing is provided, which includes amino acid sequences for six different scFv-CD39 structures, the scFvmut-CD39 structure, and four different scFv-HSA-CD39 structures (p 19-20). Although the claims are drawn to a fusion protein comprising the extracellular domain and essentially any binding protein that binds to the same GPIIb/IIIa epitope as an scFv set forth in SEQ ID NO: 1 for treatment and prevention of any inflammatory neurological disease, the experimental data (i.e., working examples 1-14) teach that autoimmune encephalomyelitis (EAE) can be used as a model for MS, that a specific targeted CD39 fusion protein (i.e., presumably the anti-CD41 scFv of SEQ ID NO: 1 conjugated to CD39, resulting in SEQ ID NO: 6) was able to reduce the onset of EAE symptoms and delayed disease progression compared to the mutant anti-CD41 scFv-CD39 fusion protein (i.e., non-targeted) in (mild) EAE models, and five alternative anti-CD41 scFv-CD39 structures based on the scFv of SEQ ID NO: 23, which is SEQ ID NO: 1 with deleted amino acid sequences of N- and C-terminus (i.e., SEQ ID NOs: 1 and 23 have the same HCDRs1-3 and LCDRs1-3). However, there is no support for the epitope of SEQ ID NO: 1, nor structures of additional binding regions which bind to the same epitope as the scFv structure of SEQ ID NO: 1 aside from SEQ ID NO: 23, which is a truncated sequence (i.e., at the N- and C-terminus) of SEQ ID NO: 1 (OA.APPENDIX).
With regard to single-chain Fv binding structures, it should be pointed out that it is well established in the art that these fusion proteins are comprised of the variable heavy (VH) and variable light (VL) chains, which are joined together by a flexible peptide linker (i.e., affects folding, stability, and target affinity). Similar to antibody structures the VH and VL chains of an scFv each consist of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Ahmad, et. al, Clin Dev Immunol, 2012, 980250, 1-15, see entire document, specifically Figure 1). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, p 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, and the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Furthermore artisans are well aware that knowledge of a given antigen (for instance a specific epitope of GPIIb/IIIa recognized by the scFv set forth in SEQ ID NO: 1) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has been discussed above, the broadest claims describe the administered product based upon what it does, such as binding GPIIb/IIIa including at the same epitope which the scFv of SEQ ID NO: 1 binds (i.e., claim 20). However, as has been made clear by recent court cases as well as USPTO guidance, describing an antibody simply by what it binds is not sufficient to provide adequate written description for the recited genus, and has been mentioned while antibodies are members of the genus of binding proteins (see claim 20) it is not limited thereto. Indeed, as taught by Edwards et al., Lescar et al., and Goel et al., the number of potential antibody structures (i.e., sequences) which can bind to the same antigen is literally astronomical, and when it is considered that the agent doing the “binding” can literally be anything including a small molecule, lipid, peptide, protein, nucleotide, etc., the size of the genus of administered reagents grows. As such describing the administered reagent based upon what it binds, where it binds, or its function as an inhibitor fails to necessarily provide a structure that gives rise to the aforementioned properties.
In this instance, the prior art supports six nondegenerate CDRs for an antibody or antibody fragment to bind its antigen. As presently written, the claims recite that the fusion protein comprises the extracellular domain of CD39 and a binding region that binds an epitope on GPIIb/IIIa recognized by a scFv consisting of the amino acid sequence of SEQ ID NO: 1. However, the specification and working examples fail to disclose a representative number of structures of the binding region which binds to a specific epitope encompassed by the language of the instant claims will have the same function (i.e., binding GPIIb/IIIa). Therefore, as presently written, the claimed broad genus of a fusion protein comprising the extracellular domain of CD39 and the binding region that binds GPIIb/IIIa at a specific epitope lacks adequate written description because there does not appear to be any correlation between the structure of the binding region and the ability to bind a specific epitope of GPIIb/IIIa (i.e., the same epitope that the scFv of SEQ ID NO: 1 binds). Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of a binding protein that binds activated GPIIb/IIIa at a specific epitope, including neutralizing GPIIb/IIIa receptor function (i.e., claim 27) or decreasing plasma levels of ADP, reducing and/or preventing platelet accumulation and/or platelet infiltration in the CNS parenchyma, etc. (i.e., claim 42), at the time the instant application was filed. Furthermore, claims 31-34 allow for mutations within the CDR regions of the binding region. The specification does not provide guidance as to how to identify antibodies that express variations of the CDRs and maintain the claimed functions. Claims 31-34 disclose the sequence of the scFv or variable regions and allow for 90% variation from the disclosed sequence, but do not offer guidance on what regions of the variable regions the sequences may differ and still function as claimed. Because these claims allow for mutations within the CDR regions of the antibody, one of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure. Logically, if applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
Enablement
Applicant’s arguments, see p 17-18, 35 USC §112, first paragraph section, filed 03SEP2025, with respect to the rejection(s) of claim(s) 19-25, 27-37, and 39-44 (claims 19 and 22 have been cancelled) under 35 USC §112(a) - enablement have been fully considered and said rejections of claims 20-21, 23-25, 27-37, and 39-44 have been withdrawn in view of the claim amendments filed as part of said response.
Applicant’s claim amendments received as part of the 03SEP2025 response have necessitated the following new grounds of rejection.
Claims 20-21, 23-25, 27-37, and 39-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
“A method of treating or preventing an inflammatory neurological disease in a subject, the method comprising
administering to the subject a fusion protein comprising an extracellular domain of CD39 linked to an anti-GPIIb/IIIa binding protein comprising the CDRs of the VH set forth in SEQ ID NO: 2 and the CDRs of the VL set forth in SEQ ID NO: 3 (i.e., SEQ ID NOs: 15-20) or
administering the fusion protein comprising an extracellular domain of CD39 linked to an anti-GPIIb/IIIa binding protein consisting of the amino acid sequence set forth in SEQ ID NO: 6;” does not reasonably provide enablement for more.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In the instance of claims 20 and 21, drawn to a method of treating or preventing an inflammatory neurological disease in a subject, comprising administering a (binding) protein comprising the extracellular domain of CD39 and any binding region that binds the same epitope of GPIIb/IIIa as the scFv of SEQ ID NO: 1 is not fully enabled because:
The breadth of the binding protein structure (i.e., fusion protein comprising the extracellular domain of CD39 and any binding region that is defined by an epitope rather than a specific structure);
The lack of support or working examples which define the epitope to which the scFv of SEQ ID NO: 1 binds to or in which alternative “binding proteins” comprising binding regions having the same epitope as the scFv of SEQ ID NO: 1 are produced;
The lack of predictability in the art; and
Therefore the undue experimentation for one of ordinary skill in the art to determine the epitope of the scFv of SEQ ID NO: 1, make, screen, and use the “binding protein.”
Claims 23-25, 27-37, and 39-44 are also rejected since they depend from claim 20, but do not remedy this deficiency.
The specification discloses the involvement of platelets and their role in inflammation as related to multiple sclerosis (MS) and the use of a recombinant fusion protein, comprising the extracellular domain of CD39 and a targeting protein binding activated GPIIb/IIIa for improved treatment of inflammatory neurological disease (see p 2-3). The specification hypothesizes that the binding protein component of the fusion protein targets and inhibits (i.e., neutralizes) natural ligand (i.e., fibrinogen/fibrin) binding to activated GPIIb/IIIa on activated platelets and the CD39 (i.e., an anti-platelet factor) component of the fusion protein enriches CD39, which together enriches CD39 to activated platelets (p 3, lines 4-6, p 24, lines 4-7). Furthermore, CD39 is also known as ectonucleoside triphosphate diphosphohydrolase-1, and is an enzyme on the cell surface, with the catalytic site facing extracellularly and GPIIb/IIIa is also known as integrin αIIbß3 and is an integrin complex found on platelets, which is formed via calcium-dependent association of GPIIb and GPIIIa and is involved in platelet activation and aggregation by binding to fibrinogen (p 22, lines 9-36). The binding protein portion comprises an antibody variable region that binds to GPIIb/IIIa, or the variable region fragment (Fv), selected from a group of: (i) a single chain fragment (scFv), (ii) dimeric scFv (di-scFv),…or (xi) an antibody (p 3, line 35 to p 4, line 13). Additionally, the fusion protein further comprises human serum albumin (i.e., HSA) resulting in the structures: HSA-scFv-CD39, scFv-HSA-CD39, or scFv-CD39-HSA (p 10, lines 5-16). Furthermore, the specification teaches treatment and prevention of inflammatory neurological disease includes administering a protein described within the specification to thereby reduce or eliminate at least one symptom or administering a protein described within the specification to thereby stop or hinder the development of at least one symptom or hinder relapse of any disorder characterized by a defect in neuronal signaling and/or neuronal dysfunction and/or neuronal cell death resulting from an inflammatory and, in some examples, an autoimmune response (p 28, lines 11-20 and p 23, lines 1-4). Additionally, exemplary inflammatory neurological diseases include multiple sclerosis, systemic lupus erythematosus (SLE), Guillain-Barre syndrome, Lamber-Eaton myasthenic syndrome, myasthenia gravis, transverse myelitis, leukodystrophy, and progressive multifocal leukoencephalopathy (p 34, lines 24-27). A key to the sequence listing is provided, which includes amino acid sequences for six different scFv-CD39 structures, the scFvmut-CD39 structure, and four different scFv-HSA-CD39 structures (p 19-20).
Working examples 1-14 teach that autoimmune encephalomyelitis (EAE) can be used as a model for MS, that a specific targeted CD39 fusion protein (i.e., presumably the anti-CD41 scFv of SEQ ID NO: 1 conjugated to CD39, resulting in SEQ ID NO: 6) was able to reduce the onset of EAE symptoms and delayed disease progression compared to the mutant anti-CD41 scFv-CD39 fusion protein (i.e., non-targeted) in (mild) EAE models, and five alternative anti-CD41 scFv-CD39 structures based on the scFv of SEQ ID NO: 23, which is SEQ ID NO: 1 with deleted amino acid sequences of N- and C-terminus (i.e., SEQ ID NOs: 1 and 23 have the same HCDRs1-3 and LCDRs1-3). Although these examples support a binding region comprising HCDRs1-3 and LCDRs 1-3 consisting of SEQ ID NOs: 15-17 and 18-20, there is no guidance provided regarding making a CD39-GPIIb/IIIa (binding) protein, wherein the structure of the binding region is unclear and then using the (binding) protein to prevent or treat an inflammatory neurological disease.
Furthermore, the literature teaches that fibrinogen, von Willebrand factor, etc. are proteins that can bind activated GPIIb/IIIa and that when discussing antibodies, antibody fragments, or single chain fragments that bind GPIIb/IIIa requires six nondegenerate CDRs to bind the antigen of interest which in this case requires significant screening. Specifically, Schwarz, et. al, teach that inhibition of activated GPIIb/IIIa-fibrinogen binding inhibits platelet aggregation; however previous GPIIb/IIIa inhibitors were limited by adverse side effects in addition to binding non-activated GPIIb/IIIa, and the newly developed single chain Fv that specifically bind activated GPIIb/IIIa overcome the previous limitations. Of note, Schwarz, et. al, teach that the scFv SCE5 subclone was developed from a phage library (i.e., two phage libraries, with serial rounds of selection to enhance the population of specific binding motifs) and bind at or near to the discontinuous fibrinogen binding site on both subunits of GPIIb/IIIa (i.e., epitope of the SCE5 subclone), wherein the similarity of HCDR3 and LCDR3 of the scFv of SEQ ID NO: 1 of the instant application are underlined in the respective CDRs of SCE5: HCDR3: CARGATYTSRSDVPDQTSFDY and LCDR3: CLLYGGGWWGVFGGG ) ((Schwarz, et. al, The FASEB Journal, 2004, p 1704-1706, see abstract, Fig 3 and Fig 4, and p 12). More generally, the art supports that scFv structures are comprised of the variable heavy (VH) and variable light (VL) chains, which are joined together by a flexible peptide linker (i.e., affects folding, stability, and target affinity). Similar to antibody structures the VH and VL chains of an scFv each consist of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Ahmad, et. al, Clin Dev Immunol, 2012, 980250, 1-15, see entire document, specifically Figure 1). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, p 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982).
Additionally, artisans are well aware that knowledge of a given antigen (for instance a specific epitope of GPIIb/IIIa recognized by the scFv set forth in SEQ ID NO: 1) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Therefore, the prior art supports that in order to define a (binding) protein comprising a binding region that binds to the same epitope as an scFv of SEQ ID NO: 1 as recited in claims 20-21, the protein binding region requires six nondegenerate CDRs, to determine a binding structure from a defined epitope is nearly impossible, and to make a binding structure that binds to a specific epitope (which in this instance is undisclosed) requires multiple phage libraries and screening steps.
Thus, one skilled in the art would be unable to make the (binding) protein and then use a method of treating or preventing an inflammatory neurological disease in a subject, comprising administering a (binding) protein comprising the extracellular domain of CD39 and any binding region that binds the same epitope of GPIIb/IIIa as the scFv of SEQ ID NO: 1 because there is no specific structure of the binding protein wherein six nondegenerate CDRs are defined. Therefore, the implementation of the invention in view of the unclear nature (i.e., epitope of SEQ ID NO: 1), breadth of variables (i.e., protein binding region), lack of predictability in the art, and lack of support in the specification and working examples, would require undue experimentation for one of ordinary skill in the art to make and use the instantly claimed invention.
With regards to claims 31-34, the specification and working examples lack support to make protein binding region wherein there is 10% variability including within the CDRs, which could then be used to treat an inflammatory neurological disease upon administration.
In the instance of claim 35, the specification and working examples lack support to make a protein binding region wherein there are only HCDRs1-3 or only LCDRs 1-3. Instead all examples support scFv structures consisting of HCDRs1-3 and LCDRs1-3.
With regards to claims 36-37, it is unclear whether any linker between 3 and 30 amino acids in length would perform similarly to the only exemplary linker of SEQ ID NO: 29 because the literature supports that there are variety of linkers that have been developed and/or are commercially available which can be flexible or rigid or can be cleavable or non-cleavable, etc. which affects the activity, efficacy, yields, and pharmacokinetics of the overall fusion protein (Chen, et al., Adv Drug Delivery Rev, 2013, 65, 1357-1369, see entire document).
Claims 41 and 43-44 drawn to the administration of the CD39-GPIIb/IIIa binding protein to a subject at risk of developing MS or prior to onset of clinical symptoms of in this instance any inflammatory neurological disease or wherein the onset of clinical symptoms is characterized by an increase in circulating platelet numbers are not fully enabled. In this instance, the specification provides exemplary characteristics for developing MS (i.e., a specific neurological disease prior to onset of clinical symptoms), such as thyroid disease, type I diabetes, and/or IBD, as well as one or more of the following characteristics: 15-60 years of age, female, a family history of MS, suffers from a viral infection (e.g., Epstein-Barr), and/or is a smoker (p14). However, the prior art supports that there is a positive causal relationship between TSH and MS, but not between FT4, hypothyroidism, or hyperthyroidism and MS (Cui, et al., Medicine, 2024, 103, 1-7), which suggests that not all thyroid diseases will result in MS. Therefore it is unclear which patients are at risk of developing MS or if it is safe for the medical provider to administer the CD39-GPIIb/IIIa binding protein to subjects that fall under the categories of being at risk of developing MS but would not have developed MS, for example. Furthermore, it is unclear how patients that are administered the CD39-GPIIb/IIIa binding protein for prophylaxis would be defined/determined for any inflammatory neurological disease and therefore to which subject the medical provider is to administer the CD39-GPIIb/IIIa binding protein to because they have no clinical symptoms (i.e., no increase in circulating platelet numbers) of MS, Alzheimer’s, Parkinson’s, meningitis, stroke, etc. (i.e., any inflammatory neurological diseases). For example, it is possible that the circulating platelet numbers fluctuate and by using increased circulating platelet numbers as evidence of onset of clinical symptoms, the medical provider is only provided a snap shot of the circulating platelet numbers at the time of measurement, which means that the medical provider could have missed an increase in circulating platelet numbers and is administering the CD39-GPIIb/IIIa binding protein after onset of clinical symptoms as defined as an increase in circulating platelet numbers. Additionally because there are no limitations regarding a patient having risk factors for said inflammatory neurological disease, if the CD39-GPIIb/IIIa binding protein were administered to a normal, healthy patient, it is unclear whether the CD39-GPIIb/IIIa binding protein could prevent the development of any inflammatory neurological disease or whether the CD39-GPIIb/IIIa binding protein is safe in normal, healthy patients.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see p 18-20, 35 USC 102 section, filed 03SEP2025, with respect to the rejection(s) of claim(s) 20, 23-25, and 41-42 under 35 USC §102 have been fully considered and said rejections of claims 20, 23-25, and 41-42 have been withdrawn in view of the claim amendments filed as part of said response, which add limitations that are not fully enabled and are also not taught in the cited art.
Claim Rejections - 35 USC § 103
Applicant’s arguments, see p 20-28, 35 USC 103 section filed 03SEP2025, with respect to the rejection(s) of claim(s) 19-36, 38-40, and 42 (claims 19, 22, and 26 have been cancelled) under 35 USC §103 have been fully considered and said rejections of claims 20-21, 23-25, 27-36, 38-40, and 42 have been withdrawn in view of the claim amendments filed as part of said response which add limitations that are not fully enabled and/or are also not taught in the cited art.
Response to Arguments
Applicant argues that the amendment to claim 20 to include that the binding region binds to the epitope of the scFv having the amino acid sequence as set forth in SEQ ID NO: 1, provided a clear structural and functional definition of the binding region and therefore no longer encompasses a broad genus of undefined “binding proteins” and the link between the structure and therapeutic effect is well established, suggesting that there was sufficient written description. Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
As set forth in the 35 USC §112(a)—written description rejection supra, the specification provides neither a representative number of the encompassed binding proteins that bind to the same epitope as the scFv of SEQ ID NO: 1, nor does it provide a descriptive of the structural features that are common to the encompassed binding region other than SEQ ID NO: 1 or the truncated version of SEQ ID NO: 1 set forth in SEQ ID NO: 23. Therefore, because the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed binding molecules, antibodies, and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Applicant argues that the office did not provide sufficient references for support of the lack of enablement, that enablement is not precluded by the necessity for some experimentation such as routine screening, and amendment of claim 20 overcomes the enablement rejection. Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
As set forth in the 35 USC §112(a)—enablement rejection supra, one of ordinary skill in the art would not be able to make the CD39-GPIIb/IIIa binding protein due to the breadth of the structures (i.e., any protein that binds to the same GPIIb/IIIa epitope as the scFv of SEQ ID NO: 1), the lack of predictability in the art (i.e., see references of record), and the lack of working examples or support in the specification that details the epitope of the scFv set forth in SEQ ID NO: 1 or additional structures that bind to said epitope. Specifically, it would require undue experimentation for one of ordinary skill in the art to determine the epitope, develop a phage library to make and screen the binding proteins that specifically bind said epitope and then conjugate said binding protein with the extracellular domain of CD39 to use in a method of treating or preventing an inflammatory neurological disease.
Allowable Subject Matter
Claim 38 is 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.
Conclusion
Claim 38 is objected to.
Claims 20-21, 23-25, and 27-37, and 39-44 are rejected.
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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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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