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
Claims 1, 19, 41, 61, 66-68, 92, 95, 104-107, and 115-119 are pending and under examination in the instant office action.
Drawings
The drawings are objected to because Fig. 37-52 refer to binding to PSMA, but teach antibody clones 1-8 that the specification. 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(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 1, 19, 41, 61, 66-68, 92, 95, 104-107, and 115-119 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.
Scope of the claimed genus
Claim 1 recites an antibody comprising a heavy chain variable domain comprising the amino acid sequences of (i) SEQ ID NOs: 1, 2, and 3, or variations with one, two, or three amino acid additions, deletions, or substitutions; (ii) SEQ ID NOs: 9, 10, and 11, or variations with one, two, or three amino acid additions, deletions, or substitutions; (iii) SEQ ID NOs: 17, 18, and 19, or variations with one, two, or three amino acid additions, deletions, or substitutions; (iv) SEQ ID NOs: 25, 26, and 27, or variations with one, two, or three amino acid additions, deletions, or substitutions; (v) SEQ ID NOs: 33, 34, and 35, or variations with one, two, or three amino acid additions, deletions, or substitutions; (vi) SEQ ID NOs: 41, 42, and 43, or variations with one, two, or three amino acid additions, deletions, or substitutions; (vii) SEQ ID NOs: 49, 50, and 51, or variations with one, two, or three amino acid additions, deletions, or substitutions; (viii) SEQ ID NOs: 57, 58, and 59, or variations with one, two, or three amino acid additions, deletions, or substitutions. The claimed sequences are not required to be CDRs, or to be in any order. In addition, the antibody does not have any target or epitope required for it to bind. The instant specification states that the terms “antibody” includes polyclonal antibodies, monoclonal antibodies, recombinant antibodies, humanized antibodies, human antibodies, chimeric antibodies, multi-specific antibodies, diabodies, scFv antibodies, and tandem single-chain variable fragment antibodies.
Claims 19, 41, 61, 68, and 92 recite an antigen binding fragment; an antibody domain; a chimeric antigen receptor comprising an antigen binding domain, a hinge, a transmembrane domain, and one or more signaling domains; a cell engaging comprising a first antigen binding domain, a linker, and a second antigen binding domain; and an antibody-drug conjugate comprising an antigen binding domain covalently linked to a drug, respectively, with identical sequence requirements of a heavy chain variable domain as described above for claim 1.
Thus, the scope of claims 1, 19, 41, 61, 68, and 92 is directed at antibodies and antigen binding fragments thereof with no specified target and with up to 3 amino acid changes allowed in the claimed sequences of the variable region, which are not required to be CDRs and may be in any order.
Regarding claims 66-67, the claims are directed at the CAR of claim 61 without further limiting the heavy chain variable domain structure. Regarding claims 95, 104-107, and 115-119, the claims are directed at compositions comprising the products of the independent claims as described above, and a method of treating a mammal having cancer, wherein said method comprises administering to said mammal a composition of claim 95 and do not further limit the structure of the heavy chain variable domain as claimed.
State of the Relevant Art
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) taught 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 taught 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 taught 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).
Further, a recitation of one, two, or three changes per SEQ ID NO: does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “one, two, or three amino acid additions, deletions, or substitutions” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. The examiner notes that while no particular antigen binding is specified by the claims, it is unclear whether the specified changes would still result in an antibody with any binding function whatsoever. A person of ordinary skill in the art would understand that an antibody, antigen binding domain, an antibody domain, a chimeric antigen receptor, and an antibody-drug conjugate all require a specific antigen target.
Regarding the structure of single-domain antibodies, Wagner HJ et al. Int J Mol Sci. 2018 19(11): 3444 teaches in the context of nanobodies, universal scaffolds have been identified, enabling the generation of robust or humanized VHH variants but, this strategy has only been applied to graft CDRs to acceptor frames obtained from animals of the same taxonomic family (page 2, last paragraph). Wagner taught the design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration, because both the heavy and light chain variable domain (VH and VL) form the antigen binding site and are involved in the recognition of the antigenic epitope (page 2, last paragraph). Furthermore, the framework plays an important role in CDR conformation and orientation and distinct framework residues often contribute directly to antigen binding (page 2, last paragraph). Thus, single-domain antibodies still require defined CDRs.
As taught by Noël et. al. "Global analysis of VHHs framework regions with a structural alphabet." Biochimie 131 (2016): 11-19, VHH domains are the variable regions of Heavy Chain Antibodies (HCAbs), which are immunoglobulin proteins lacking a light chain and a CH1 domain. Noël et. al. teaches: “These VHHs are composed of 4 regions whose sequences and structures are defined as conserved (called Framework Regions, FRs). In addition, VHHs contain three connecting regions showing high variability both in sequence content and structure conformation. These regions are complementary to the antigen surface and are called Complementarity Determining Regions or CDRs). Fig. 1 underlines in 3D (see Fig. 1A [8], [9], [10], [11], [12], [13], [14], [15], [16]) and 2D (see Fig. 1B) similarities of VHHs to conventional antibodies” (Introduction, 3rd para. and Fig. 1). Noël et. al. teaches that the framework regions (FRs) of VHHs are considered to be “constant” regions with a conserved structure, and in some cases a conserved sequence. The FR identity ranged from 76.9% for FR2 to 94.4% for FR4, and the whether there was variation in the amino acids was constrained to particular positions (Fig. 2). In particular, there is a structural pattern that is conserved in the FRs, suggesting that these are not dispensable for antigen-binding function: “Each of the four FRs is associated to a main structural pattern, which can be considered as canonical, but represents only 40, 84, 63, and 38%, leading to the characterization to variant patterns ranging from 6 to 19. Among some of them, we observe some similarity and the final number of variant patterns could be slightly reduced. However, clearly some are really outliers at more than 1 Å from the main structural pattern and could have strong impact of the proposition of structural models” (Discussion, 6th para.).
Although there is no specific binding function required of the antibodies in the claims, the specification was consulted to determine whether the antibodies that are described in the specification have a particular target. The instant specification teaches that the antibodies are specific for PRTG (e.g. p. 1 lines 8-17) In regard to anti-PRTG antibodies, a few other anti- PRTG antigen binding sites are known in the art. For example, US 20050287664 teaches an antagonist antibody wherein the antibody recognizes Shen-Dan (synonymous with PRTG as evidenced by Genecards.org “PRTG gene”). The art also teaches that PRTG is upregulated in gastric cancer and H. pylori-infected tissues (Xiang, Tian, et al. "The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway." Cell death & disease 12.2 (2021): 150; Abstract; IDS dated 4/15/2025). Xiang et. al. further teaches that high PRTG expression is associated with decreased survival for 152 gastric cancer patients (Fig. 1F-H). Xiang et. al. teaches that the downstream molecular mechanism of PRTG is the cGMP/PKG pathway and that inhibitors of sGC or PKG can block the increase of cGMP induced to PRTG overexpression (Fig. 5) and increased the effect of chemotherapy against PRTG-overexpressing cells (Fig. 6). There is no other support in the literature of record for antibodies as antagonists of PRTG or a method of treating cancer using antibodies against PRTG.
Summary of Species disclosed in the original specification
The instant specification discloses 8 single-domain antibodies that specifically bind to PRTG (Example 1, clones 1-8). None of the VH antibodies bind to 293T cells lacking human PRTG or are shown to bind to a target other than PRTG. None of the antibodies is an antibody comprising both a VH and a VL.
The specification further discloses chimeric antigen receptors comprising the VH antibody domains clones 1-8 (Example 3). The CARs were expressed in human T cells and the specification teaches that CAR #6B and CAR #7B exhibited target cell killing without control cells killing, while in another experiments CAR #2B, CAR #4B, and CAR #6B exhibited target cel killing with limited control cell killing in a second experiment (Example 3).
The specification additionally teaches the use of clones 1-8 to make BiTEs to comprising an anti-PRTG domain and an anti-T cell domain (e.g. anti-CD3 scFv). BiTEs #1, #4, and #7 promoted specific killing of PRTG+ target cells (Example 4).
The specification prophetically discloses the antibodies in the formats of BiKEs (bispecifics with an NK cell recruitment domain, Example 5), antibody-drug conjugates (e.g. p. 13 lines 10-18), and Ig antibodies with heavy and light chain variable domains (e.g. Fig. 11) and heavy and light chain constant regions. The specification also prophetically discloses CDRs “consisting essentially of” the CDRs of clones 1-8 ( Tables 1-24). There are no specific VH antibodies comprising any of these CDRs shown; none of these additional CDRs are tested in any combination of 3 specific CDRs, or shown to have any target binding to any epitope. It would not have been predictable a priori which of the recited CDRs produces a functional antibody and what target that antibody would bind to. As described in the state of the art section above, a person of ordinary skill in the art would expect that many of the claimed antibodies would not bind to the target that is the focus of the instant specification, and it would not have been predictable which other targets the entire genus of claimed antibody species may bind to. It would also not have been predictable how the instant single domain antibodies may fold or interact when used in a traditional VH/VL antibody.
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 each of the 3 CDRs of the single domain antibodies of clones 1-8 or any swaps in the order of the CDRs.
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 antibodies comprising a heavy chain variable domain comprising the sequences claimed with any structure as recited in the scope of the claim. There is a lack of structures that are not single-domain antibodies or antigen-binding fragments thereof (e.g., comprising a VL); there is a lack of heavy chain variable regions in which the instantly claimed sequences are not CDR1, CDR2, and CDR3 in the recited order. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR 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 claims 1, 19, 41, 61, 68, and 92 at the time of filing. Regarding claims 66-67, 95, 104-107, and 115-119 the claims are ultimately dependent on the rejected claims 1, 19, 41, 61, 68, and 92 without narrowing the claimed subject matter and thus are also rejected.
The examiner suggests obviating this rejection by 1) reciting that the antibodies or antigen binding fragments thereof are single-chain or VHH antibodies; 2) specifying that the claimed sequences of each clone are the CDR regions of the heavy chain variable fragment of the single-chain antibody; and 3) requiring the complete sequence of each CDR without additions, substitutions, or deletions in the order of CDR1, CDR2, and CDR3.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 19, 41, 61, 66-68, 92, 95, 104-107, and 115-119 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:
single domain antibodies or antigen-binding domains thereof comprising a complete set of 3 CDRs specified by SEQ ID NO of clones 1-8 (Figs. 2-9) without additions, substitutions, or deletions or chimeric antigen receptors, cell engagers, and antibody-drug conjugates comprising the single-domain antibody or antigen binding domain thereof)
A method of treating a mammal having a PRTG-positive gastric cancer or medulloblastoma comprising administering a T cell or an NK cell comprising a CAR comprising the single-domain antibody or antigen-binding domain thereof of (1) or a cell engager comprising the single-domain antibody or antigen-binding domain thereof of (1) and a second antigen-binding domain that specifically binds an antigen on a T cell or an NK cell
does not reasonably provide enablement for:
Any generic antibody comprising a heavy chain variable domain comprising the amino acid sequences in any order and at any position (including outside of the CDRs), wherein the antibody is not required to have any binding function to PRTG and may comprise up to 3 substitutions, additions, or deletions in each of the claimed heavy chain variable domain sequences
A method of treating a mammal having any generic cancer that may or may not have any antigen expression profile comprising administering any generic antibody, antibody domain, or antigen-binding fragment thereof comprising the heavy chain variable region of (1) with no specified structure or function; comprising administering an ADC comprising the sequences of (1); or comprising administering any generic cell comprising a CAR.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Scope of the claimed genus and nature of the invention
Claim 1 recites an antibody comprising a heavy chain variable domain comprising the amino acid sequences of (i) SEQ ID NOs: 1, 2, and 3, or variations with one, two, or three amino acid additions, deletions, or substitutions; (ii) SEQ ID NOs: 9, 10, and 11, or variations with one, two, or three amino acid additions, deletions, or substitutions; (iii) SEQ ID NOs: 17, 18, and 19, or variations with one, two, or three amino acid additions, deletions, or substitutions; (iv) SEQ ID NOs: 25, 26, and 27, or variations with one, two, or three amino acid additions, deletions, or substitutions; (v) SEQ ID NOs: 33, 34, and 35, or variations with one, two, or three amino acid additions, deletions, or substitutions; (vi) SEQ ID NOs: 41, 42, and 43, or variations with one, two, or three amino acid additions, deletions, or substitutions; (vii) SEQ ID NOs: 49, 50, and 51, or variations with one, two, or three amino acid additions, deletions, or substitutions; (viii) SEQ ID NOs: 57, 58, and 59, or variations with one, two, or three amino acid additions, deletions, or substitutions. The claimed sequences are not required to be CDRs, or to be in any order. In addition, the antibody does not have any target or epitope required for it to bind. The instant specification states that the terms “antibody” includes polyclonal antibodies, monoclonal antibodies, recombinant antibodies, humanized antibodies, human antibodies, chimeric antibodies, multi-specific antibodies, diabodies, scFv antibodies, and tandem single-chain variable fragment antibodies.
Claims 19, 41, 61, 68, and 92 recite an antigen binding fragment; an antibody domain; a chimeric antigen receptor comprising an antigen binding domain, a hinge, a transmembrane domain, and one or more signaling domains; a cell engaging comprising a first antigen binding domain, a linker, and a second antigen binding domain; and an antibody-drug conjugate comprising an antigen binding domain covalently linked to a drug, respectively, with identical sequence requirements of a heavy chain variable domain as described above for claim 1.
Thus, the scope of claims 1, 19, 41, 61, 68, and 92 is directed at antibodies and antigen binding fragments thereof with no specified target and with up to 3 amino acid changes allowed in the claimed sequences of the variable region, which are not required to be CDRs and may be in any order.
Regarding claims 66-67, the claims are directed at the CAR of claim 61 without further limiting the heavy chain variable domain structure. Regarding claims 95, 104-107, and 115-119, the claims are directed at compositions comprising the products of the independent claims as described above, and a method of treating a mammal having a generic cancer, wherein said method comprises administering to said mammal a composition of claim 95 and do not further limit the structure of the heavy chain variable domain as claimed. Claim 95 includes a generic composition comprising any antibody of claim 1, antigen binding fragment of claim 19, antibody domain of claim 41, any generic cell of claim 66, or any generic ADC of claim 92. Regarding methods of treatment, claim 105 specifies that the mammal is a human, claim 104 specifies that the cancer is a PRTG+ cancer. Claim 107 narrows the scope to a PRTG+ gastric cancer and PRTG+ medulloblastoma and thus partially resolved the scope of enablement regarding the generic cancer, but does not address the scope of enablement issues for the antibody binding domain structure and the variety of different forms of antibody treatment modalities claimed (e.g. the claim reads on a method of treating comprising administering a naked scFv antibody with a binding domain that has an undescribed VL and that may bind any antigen, where native IgG antibodies cannot predictably treat cancer).
State of the relevant art; level of ordinary skill; and level of predictability in the art
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) taught 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 taught 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 taught 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).
Further, a recitation of one, two, or three changes per SEQ ID NO: does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “one, two, or three amino acid additions, deletions, or substitutions” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. The examiner notes that while no particular antigen binding is specified by the claims, it is unclear whether the specified changes would still result in an antibody with any binding function whatsoever. A person of ordinary skill in the art would understand that an antibody, antigen binding domain, an antibody domain, a chimeric antigen receptor, and an antibody-drug conjugate all require a specific antigen target.
Regarding the structure of single-domain antibodies, Wagner HJ et al. Int J Mol Sci. 2018 19(11): 3444 teaches in the context of nanobodies, universal scaffolds have been identified, enabling the generation of robust or humanized VHH variants but, this strategy has only been applied to graft CDRs to acceptor frames obtained from animals of the same taxonomic family (page 2, last paragraph). Wagner taught the design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration, because both the heavy and light chain variable domain (VH and VL) form the antigen binding site and are involved in the recognition of the antigenic epitope (page 2, last paragraph). Furthermore, the framework plays an important role in CDR conformation and orientation and distinct framework residues often contribute directly to antigen binding (page 2, last paragraph). Thus, single-domain antibodies still require defined CDRs.
As taught by Noël et. al. "Global analysis of VHHs framework regions with a structural alphabet." Biochimie 131 (2016): 11-19, VHH domains are the variable regions of Heavy Chain Antibodies (HCAbs), which are immunoglobulin proteins lacking a light chain and a CH1 domain. Noël et. al. teaches: “These VHHs are composed of 4 regions whose sequences and structures are defined as conserved (called Framework Regions, FRs). In addition, VHHs contain three connecting regions showing high variability both in sequence content and structure conformation. These regions are complementary to the antigen surface and are called Complementarity Determining Regions or CDRs). Fig. 1 underlines in 3D (see Fig. 1A [8], [9], [10], [11], [12], [13], [14], [15], [16]) and 2D (see Fig. 1B) similarities of VHHs to conventional antibodies” (Introduction, 3rd para. and Fig. 1). Noël et. al. teaches that the framework regions (FRs) of VHHs are considered to be “constant” regions with a conserved structure, and in some cases a conserved sequence. The FR identity ranged from 76.9% for FR2 to 94.4% for FR4, and the whether there was variation in the amino acids was constrained to particular positions (Fig. 2). In particular, there is a structural pattern that is conserved in the FRs, suggesting that these are not dispensable for antigen-binding function: “Each of the four FRs is associated to a main structural pattern, which can be considered as canonical, but represents only 40, 84, 63, and 38%, leading to the characterization to variant patterns ranging from 6 to 19. Among some of them, we observe some similarity, and the final number of variant patterns could be slightly reduced. However, clearly some are really outliers at more than 1 Å from the main structural pattern and could have strong impact of the proposition of structural models” (Discussion, 6th para.).
Although there is no specific binding function required of the antibodies in the claims, the specification was consulted to determine whether the antibodies that are described in the specification have a particular target. The instant specification teaches that the antibodies are specific for PRTG (e.g. p. 1 lines 8-17) In regard to anti-PRTG antibodies, a few other anti- PRTG antigen binding sites are known in the art. For example, US 20050287664 teaches an antagonist antibody wherein the antibody recognizes Shen-Dan (synonymous with PRTG as evidenced by Genecards.org “PRTG gene”). The art also teaches that PRTG is upregulated in gastric cancer and H. pylori-infected tissues (Xiang, Tian, et al. "The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway." Cell death & disease 12.2 (2021): 150; Abstract; IDS dated 4/15/2025). Xiang et. al. further teaches that high PRTG expression is associated with decreased survival for 152 gastric cancer patients (Fig. 1F-H). Xiang et. al. teaches that the downstream molecular mechanism of PRTG is the cGMP/PKG pathway and that inhibitors of sGC or PKG can block the increase of cGMP induced to PRTG overexpression (Fig. 5) and increased the effect of chemotherapy against PRTG-overexpressing cells (Fig. 6). There is no other support in the literature of record for antibodies as antagonists of PRTG or a method of treating cancer using antibodies against PRTG that would help enable the methods of treating comprising the instant anti-PRTG antibodies.
Regarding methods of treating generic cancers with a naked antibody or antigen binding fragment thereof that may or may not bind to a particular target, it is known in the field that typically treatment of cancer requires some sort of cytotoxic ability of the antibody in addition to binding of a tumor-associated antigen that is expressed by the cancer. Thomas, et. al. "Antibody–drug conjugates for cancer therapy." The Lancet Oncology 17.6 (2016): e254-e262 teaches “Most monoclonal antibodies by themselves have little antitumour activity, even after binding to the target antigen. Some notable exceptions include monoclonal antibodies to HER2, EGFR, and CD20, which have remarkable activity against tumours expressing these antigens. However, despite scant antitumour activity of monoclonal antibodies, their specificity for the target antigen makes them useful cancer therapeutic agents” (Introduction, ¶1). As described above, it would not have been predictable a priori whether any of the antibodies encompassed by the claims bind to HER2, EGFR, and CD20. Thomas et. al. also teach that an important consideration for ADC design is that the “Target should be expressed preferentially on tumour cells over non-malignant cells; high-level expression is advantageous, although not necessary”. A person of ordinary skill in the art would also understand that this advantage would apply to other formats of antibody therapeutics beyond ADCs. The instant claims, as described above, currently encompass 1) antibodies with unknown target epitopes; 2) methods of treating cancer with naked antibodies and antigen-binding fragments thereof with no known cytotoxic payload; and 3) cancers that do not express the target antigen (which, of the described and enabled antibodies, is PRTG).
Regarding methods of treating with an ADC comprising the antibody, Tsuchikama K et al. Antibody-drug conjugates: recent advances in conjugation and linker chemistries (Protein & Cell 2018 9(1) 33–46) teaches ADCs require internalization of the antibody to release the cytotoxic payload. While ADC bystander killing of cancer cells can occur, the initial internalization of the payload is required for effective release of cleavable enzymes (Fig. 1). In addition, Li, Fu, et al. "Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models." Cancer research 76.9 (2016): 2710-2719 teaches antibody-drug conjugates (ADC) comprise targeting antibodies armedwith potent small-molecule payloads (Abstract). Li teaches membrane permeability and the ability of the released payload to diffuse through the tumor are required for bystander killing and it is important to evaluate engineered payload for their membrane permeability and bystander killing (page 2717, left column, second to last paragraph). Li et. al. teaches that the amount of released MMAE also determines the antitumor activity of ADC in vivo, independent of antigen expression, suggesting the ADC design shall aim to improve intratumoral payload delivery. The Applicant has not shown that the claimed antibody can be effectively used in a method of treatment of cancer in a subject as an ADC. The absence of internalization would lead to an inability of the payload to be released intracellularly within the cancer cell. Further, reliance on potential extracellular release of payloads in the absence of internalization would lead to enhanced systemic toxicity that would prevent an effective treatment with the ADC comprising the claimed antibody.
Therefore, while the level of ordinary skill in the art is high (e.g. a PhD in molecular biology or equivalent), the level of unpredictability in the art is also extremely high and a person of ordinary skill in the art would not be able to make and use all of the antibodies and methods of treating cancer as claimed.
Summary of species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and the quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification discloses 8 single-domain antibodies that specifically bind to PRTG (Example 1, clones 1-8). None of the VH antibodies bind to 293T cells lacking human PRTG or are shown to bind to a target other than PRTG. None of the antibodies is a antibody comprising both a VH and a VL. Even when limited to PRTG antibodies, the instant specification describes only PRTG+ medulloblastoma and the art describes PRTG+ gastric cancer. There are no other cancers of record or disclosed to express PRTG.
The specification further discloses chimeric antigen receptors comprising the VH antibody domains clones 1-8 (Example 3). The CARs were expressed in human T cells and the specification teaches that CAR #6B and CAR #7B exhibited target cell killing without control cells killing, while in another experiments CAR #2B, CAR #4B, and CAR #6B exhibited target cel killing with limited control cell killing in a second experiment (Example 3). The specification teaches that CAR #1B, CAR #2B, CAR#3B, CAR #4B, CAR #5B, and CAR #8B showed less killing in one experiment (Example 3).
The specification additionally teaches the use of clones 1-8 to make BiTEs to comprising an anti-PRTG domain and an anti-T cell domain (e.g. anti-CD3 scFv). BiTEs #1, #4, and #7 promoted specific killing of PRTG+ target cells (Example 4).
The specification prophetically discloses the antibodies in the formats of BiKEs (bispecifics with an NK cell recruitment domain, Example 5), antibody-drug conjugates (e.g. p. 13 lines 10-18), and Ig antibodies with heavy and light chain variable domains (e.g. Fig. 11) and heavy and light chain constant regions. The specification also prophetically discloses CDRs “consisting essentially of” the CDRs of clones 1-8 ( Tables 1-24). There are no specific VH antibodies comprising any of these CDRs shown; none of these additional CDRs are tested in any combination of 3 specific CDRs, or shown to have any target binding to any epitope. It would not have been predictable a priori which of the recited CDRs produces a functional antibody and what target that antibody would bind to. As described in the state of the art section above, a person of ordinary skill in the art would expect that many of the claimed antibodies would not bind to the target that is the focus of the instant specification, and it would not have been predictable which other targets the entire genus of claimed antibody species may bind to. It would also not have been predictable how the instant single domain antibodies may fold or interact when used in a traditional VH/VL antibody.
Lastly, there are no methods of treating cancer in vivo by administering to a mammal disclosed whatsoever comprising any of the instant clones #1-#8 in any format.
Thus, a person of ordinary skill in the art would have to 1) determine the target epitope of each of the antibodies claimed other than clones 1-8; and 2) experimentally determine the cytotoxicity against all generic cancers and cancers expressing the generic target antigen in all of the claimed formats (e.g. testing each antibody in a method of treating cancer comprising administering a skin cell comprising the chimeric antigen receptor), and 3) finally determine whether that in vitro target, antibody, and antibody format is suitable for translation to administer to a mammal in a method of treating cancer. This would constitute undue experimentation.
Conclusion
Applicant does not have enablement for all of the antibodies and the methods of treating cancer comprising administering the antibodies to a mammal as claimed. It would take undue experimentation to determine the target epitope of all of the claimed antibodies and to determine methods of treating any generic cancer in any mammal with no claimed target epitope in any and all of the antibody formats (e.g. a naked antigen-binding fragment) as claimed.
Allowable Subject Matter
A heavy chain-only antibody or antigen-binding fragment thereof wherein the heavy chain only variable domain comprises complementarity determining regions (CDRs) of CDR1, CDR2, and CDR3 as follows:
the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively;
the amino acid sequences set forth in SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively;
the amino acid sequences set forth in SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19, respectively;
the amino acid sequences set forth in SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively;
the amino acid sequences set forth in SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35, respectively;
the amino acid sequences set forth in SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively;
the amino acid sequences set forth in SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, respectively; or
the amino acid sequences set forth in SEQ ID NO:57, SEQ ID NO: 58, and SEQ ID NO:59, respectively;
is free of the prior art.
Conclusion
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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