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 .
DETAILED ACTION
Claims 18-46 are pending in the instant application.
Claims 1-17 have been cancelled.
Claim Status
New claims 18-46 would still be encompassed under the previous Group I drawn to an antigen-binding molecule comprising an antigen-binding domain whose antigen-binding activity changes in a 5’-methyladenosine (MTA)-dependent manner previously selected by the Applicant on 1/10/2025
Claim Rejections Withdrawn
The claim rejections of claims 1-6 are moot in view of claim cancelation.
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.
Claims 18-21, 23-39, and 46 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.
Regarding instant claims 18 and 46, in the last two lines of the claim, the claim recites that the antigen-binding molecule does not comprise all three CDRs of SEQ ID NO:31 or all three CDRs of SEQ ID NO:32, but does not describe the sequence of the CDRs that are excluded. CDRs are defined by separate definition schemes that have separate CDR sequences depending on whether the definition scheme of Kabat, Chothia, or IMGT are used. Thus, the meets and bounds of the claim are unclear and the claim is indefinite.
Claims 19-21 and 23-39 are dependent on claim 18 without further narrowing the claim outside of the indefinite subject matter and are also rejected.
To promote compact prosecution, the CDR amino acid position will be assigned according to the Kabat definition scheme as taught in the instant specification on page 49 paragraph 34. The Examiner will interpret the calculated Kabat definition scheme of a VH of instant SEQ ID NO:31 and a VL of SEQ ID NO:32 as comprising a VH of H-CDR1-3 of NYAMG; IIGADSSTWYPSWVKG; and GRFVGYTNAFDP and a VL of L-CDR1-3 of QSSQSVWNNNYLS; DASTLAS; HGSYANSGWYDNA. The Applicant is required to detail the definition scheme and sequence that is to be excluded.
Claim Rejections – 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18-46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 18, 22, 40, and 44-46, the antigen-binding molecule comprising an antigen-binding domain that binds to MTA and further binds to an antigen that is a peptide, polypeptide or protein: a) claims binding to an undefined target with a VH and VL comprised of a set of 6 complementarity-determining regions (CDRs) that permit changes within the CDR for binding, which is unpredictable; and b) does not claim a CDR and framework region that provides the necessary structure of an antigen-binding domain for MTA binding. The claimed antigen-binding molecules would require further unpredictable empirical testing to exchange CDR residues for each individual protein target to potentially obtain an effective antigen-binding molecule. Further empirical testing for successful antigen-binding molecules secretion would also be required. While claims 40 and 44-46 do not specify the required binding antigens, the incomplete CDR sequences claimed do not enable predictable binding of antigens. Claims 19-21, 23-39, and 41-43 are dependent on claims 18 or 40 without further defining the full CDR and framework structure that allows MTA-dependent antigen binding to a defined target. The sequence of antibody framework and CDR regions that allow MTA-dependent antigen binding changes are not claimed.
Scope of the claimed genus
Regarding claims 18, 22, 40, and 44-46, the antigen-binding molecule comprising an antigen-binding domain that binds MTA, wherein the antigen binding domain further binds to an antigen that is a peptide, a polypeptide, or a protein, wherein the antigen binding domain comprises a VH and VL, wherein the VH and VL comprise H-CDR1-3 and L-CDR1-3 sequences that include variable options for the H- and L-CDR claimed sequences. Claims 19-21, 23-39, and 41-43 are dependent on claim 18 or 40 without further defining the full CDR and framework structure that allows MTA-dependent antigen binding to a defined target. The sequence of antibody framework and CDR regions that allow MTA-dependent antigen binding changes are not claimed.
State of the Relevant Art
The claims are directed to a genus of “antigen-binding molecules” that comprise an “antigen-binding domain” with a structure that is variable within the CDR and may use any VH or VL framework. The claims indicate the antigen-binding domain may bind any peptide, polypeptide, or protein. The claim lacks a core sequence structure of an antigen-binding molecule that results in MTA-dependent changes to regulate antigen binding activity. The full sequence of and antibody framework and CDR region that allow MTA-dependent antigen binding changes are not claimed.
Regarding adenosine analog-dependent antibody binding, WO 2015083764 (Igawa T et al. IDS reference) taught a small molecule switch antibody does not bind to the antigen in a normal environment where small molecules are present, but binds to the antigen in target tissues where small molecules are present at high concentrations. Igawa taught an antigen-binding molecule SMB0002 that binds ADP and ATP comprising an antigen binding domain of a variable heavy chain comprising SEQ ID NO:30 and a variable light chain comprising SEQ ID NO:31 (pages 221-222, paragraph 479-483 and Figure 8-10) and the antigen-binding molecule in a pharmaceutical composition (pages 201-202, paragraph 411). Igawa taught by constructing a library using antibodies that exhibit binding ability to ATP as a template, it was thought that antibodies that exhibit binding ability to antigens could be obtained only in the presence of ATP (page 222, paragraph 484). Igawa taught because SMB0002 binds not only to adenosine and AMP but also to ADP and ATP, it is expected to have binding activity to cAMP and ATP-gamma-S, whose structure is similar to AMP, ADP, ATP and adenosine (page 237, paragraph 511). Igawa taught Fig. 43 shows the binding amount of 1 mM of each clone to IL-6R in the presence or absence of 1 mM ATP, wherein no binding to IL-6R was observed in the absence of ATP for antibodies such as 6RDL3C5-4_11 (SEQ ID NO:125 and SEQ ID NO:126) (pages 311-312, paragraph 692-694). Further, ATP analogs also effected antigen binding wherein ADP, AMP, and cAMP promoted antigen binding in Fig. 43. Thus, ATP has the property of binding to IL-6R as a switch in 6RDL3C5-4_11 and adenosine-analog dependent switches are known to 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. Antibody Structure and Function: The Basis for Engineering Therapeutics. 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, as Chiu taught both the antigen and CDR structure undergo conformational changes due to CDR binding above, conformational changes due to MTA interactions with the antigen would further enhance the level of unpredictability in the claimed antigen-binding domain.
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Summary of Species disclosed in the original specification
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.
“[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.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). 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 “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
Applicant discloses antibodies that bind certain protein antigens, wherein the binding of the antibody to the protein antigen depends upon the concentration of a small molecule that is 5'-methylthioadenosine (MTA) (also referred to as MTA switch
antigen-binding molecules (Specification, page 154, lines 19-21)). The working Examples show the screening process to select antibodies that bind the protein antigens IL-6, IL-6R, and HAS in the presence of MTA.
Instant Fig. 2 taught that MTA was elevated in MTAP-deficient cancer cells and after 48 hours in culture, MTA levels approached 10 µM in Mia-PaCa2 cancer cells.
Instant Fig. 4 taught that MTA was elevated in tumors of MTAP-deficient cell Mia-PaCa2 cancer cells and instant Fig. 5 taught MTA was elevated in MTAP-deficient human tumors.
Example 2-3 taught an hIL-6R MTA-dependent antibody of C03H-BH076N17/C03L-KT0 comprising a heavy chain variable region of SEQ ID NO:54 and a light chain variable region of SEQ ID NO:55 was identified, which bound hIL-6R in the presence of increasing concentration of MTA, but not adenosine, in Fig. 7. The antibody required about 30 µM MTA to begin to bind its target over background levels. This contrasts with Mia-PaCa2 tumors which were shown to have less than 0.1 µM MTA present in the tumor.
Example 4-2 and 6-7-5 taught MTA-dependent antibodies that target hIL-6R, hIL-6 and hIgA (page 245, paragraph 537, page 247, paragraph 543, and page 280, paragraph 623-624),
Different antibody libraries were used to obtain MTA-dependent antibodies.
S02 library
Table 14 on page 247 taught after several rounds of panning to identify clones with MTA-dependent binding there is a variable number of clones that bind to the antigen in an MTA or MTA and adenosine specific manner from the S02 library.
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275
684
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Antibody sequences of specific clones are taught in Table 15 on page 249.
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97
970
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While dissociation constants are taught in Table 16 on page 250
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496
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M30 library
Table 31 on pages 280-281 taught after several rounds of panning to identify clones with MTA-dependent binding there is a variable number of clones that bind to the antigen in an MTA or MTA and adenosine specific manner from the M30 library.
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676
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49
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Table 31 shows that a large majority of the antibody clones for hIL-6 and hIgA were unsuccessful at binding an antigen in an MTA specific manner. Thus, the generation of a successful antibody that is MTA-dependent is unpredictable.
Antibody sequences of specific clones are taught in Table 15 on page 249.
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97
970
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While dissociation constants are taught in Table 16 on page 250
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183
496
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Instant Figs 28-30 taught that the hIL-6R antibody is MTA dependent and can target a bispecific hIL-6R-CD3 antibody to T cells to activate the T cells in the presence of exogenous MTA, wherein the concentrations were 300 µM MTA (Fig 28) and 10-100 µM MTA (Fig 29-30).
It is unknown if the MTA-dependent antibodies can effectively bind their targets to produce phenotypic effects at physiologically relevant concentrations of MTA.
Accordingly, Applicant has demonstrated that antibodies that bind to three possible protein antigens of interest in the presence of MTA "switches" that the art had reported occurred at higher levels in tumor tissue could be isolated from antibody libraries using Applicant’s selection technique. But even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
Here, the art did not recognize, and Applicant has not described, a full structure shared by the claimed antigen-binding molecules whose antigen-binding activity changes in a 5'-methylthioadenosine (MTA)-dependent manner as broadly claimed that would correlate with the functional properties recited and allow binding to any protein target. The structure of an antibody does not allow one of skill in the art to immediately envision which members of the genus of antibodies would have the claimed functional MTA dependent activities and which would not for framework and CDRs. Accordingly, Applicant has not provided a sufficient structure/function correlation to adequately describe the invention as broadly claimed.
It is acknowledged that Applicant has provided several species falling within the claimed genus. The antibodies described were shown to have the function of binding one of three protein antigens, IL-6, IL-6R, and HSA, in the presence of the small molecule “switch” MTA. The claims, in contrast, encompass antibodies that bind any antigen and whose binding is dependent upon MTA with a variable CDR and any framework. Therefore, the claims encompass highly diverse species of antigen-binding molecules and the species described, limited to antibodies that bind three protein antigens, cannot be considered representative of the genus.
For these reasons, the specification does not provide an adequate written description of the genus as broadly claimed.
Claims 18-46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding claims 18, 22, 40, and 44-46, the antigen-binding molecule comprising an antigen-binding domain that binds to MTA and further binds to an antigen that is a peptide, polypeptide or protein: a) claims binding to an undefined target with a VH and VL comprised of a set of 6 complementarity-determining regions (CDRs) that permit changes within the CDR for binding, which is unpredictable; and b) does not claim a CDR and framework region that provides the necessary structure of an antigen-binding domain for MTA binding. The claimed antigen-binding molecules would require further unpredictable empirical testing to exchange framework and CDR residues for each individual protein target to potentially obtain an effective antigen-binding molecule. Further empirical testing for successful antigen-binding molecules secretion would also be required. While claims 40 and 44-46 do not specify the required binding antigens, the incomplete CDR sequences claimed does not enable predictable binding of antigens. Claims 19-21, 23-39, and 41-43 are dependent on claims 18 or 40 without further defining the full CDR and framework structure that allows MTA-dependent antigen binding to a defined target. The sequence of antibody framework and CDR regions that allow MTA-dependent antigen binding changes are not claimed.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Regarding claims 18, 22, 40, and 44-46, the antigen-binding molecule comprising an antigen-binding domain that binds MTA, wherein the antigen binding domain further binds to an antigen that is a peptide, a polypeptide, or a protein, wherein the antigen binding domain comprises a VH and VL, wherein the VH and VL comprise H-CDR1-3 and L-CDR1-3 sequences that include variable options for the H- and L-CDR claimed sequences. Claims 19-21, 23-39, and 41-43 are dependent on claim 18 or 40 without further defining the full CDR and framework structure that allows MTA-dependent antigen binding to a defined target. The sequence of antibody framework and CDR regions that allow MTA-dependent antigen binding changes are not claimed.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The claims are directed to a genus of “antigen-binding molecules” that comprise an “antigen-binding domain” with a structure that is variable within the CDR and may use any VH or VL framework. The claims indicate the antigen-binding domain may bind any peptide, polypeptide, or protein. The claim lacks a core sequence structure of an antigen-binding molecule that results in MTA-dependent changes to regulate antigen binding activity. The full sequence of and antibody framework and CDR region that allow MTA-dependent antigen binding changes are not claimed.
Regarding adenosine analog-dependent antibody binding, WO 2015083764 (Igawa T et al. IDS reference) taught a small molecule switch antibody does not bind to the antigen in a normal environment where small molecules are present, but binds to the antigen in target tissues where small molecules are present at high concentrations. Igawa taught an antigen-binding molecule SMB0002 that binds ADP and ATP comprising an antigen binding domain of a variable heavy chain comprising SEQ ID NO:30 and a variable light chain comprising SEQ ID NO:31 (pages 221-222, paragraph 479-483 and Figure 8-10) and the antigen-binding molecule in a pharmaceutical composition (pages 201-202, paragraph 411). Igawa taught by constructing a library using antibodies that exhibit binding ability to ATP as a template, it was thought that antibodies that exhibit binding ability to antigens could be obtained only in the presence of ATP (page 222, paragraph 484). Igawa taught because SMB0002 binds not only to adenosine and AMP but also to ADP and ATP, it is expected to have binding activity to cAMP and ATP-gamma-S, whose structure is similar to AMP, ADP, ATP and adenosine (page 237, paragraph 511). Igawa taught Fig. 43 shows the binding amount of 1 mM of each clone to IL-6R in the presence or absence of 1 mM ATP, wherein no binding to IL-6R was observed in the absence of ATP for antibodies such as 6RDL3C5-4_11 (SEQ ID NO:125 and SEQ ID NO:126) (pages 311-312, paragraph 692-694). Further, ATP analogs also effected antigen binding wherein ADP, AMP, and cAMP promoted antigen binding in Fig. 43. Thus, ATP has the property of binding to IL-6R as a switch in 6RDL3C5-4_11 and adenosine-analog dependent switches are known to 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. Antibody Structure and Function: The Basis for Engineering Therapeutics. 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, as Chiu taught both the antigen and CDR structure undergo conformational changes due to CDR binding above, conformational changes due to MTA interactions with the antigen would further enhance the level of unpredictability in the claimed antigen-binding domain.
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant discloses antibodies that bind certain protein antigens, wherein the binding of the antibody to the protein antigen depends upon the concentration of a small molecule that is 5'-methylthioadenosine (MTA) (also referred to as MTA switch
antigen-binding molecules (Specification, page 154, lines 19-21)). The working Examples show the screening process to select antibodies that bind the protein antigens IL-6, IL-6R, and HAS in the presence of MTA.
Instant Fig. 2 taught that MTA was elevated in MTAP-deficient cancer cells and after 48 hours in culture, MTA levels approached 10 µM in Mia-PaCa2 cancer cells.
Instant Fig. 4 taught that MTA was elevated in tumors of MTAP-deficient cell Mia-PaCa2 cancer cells and instant Fig. 5 taught MTA was elevated in MTAP-deficient human tumors.
Example 2-3 taught an hIL-6R MTA-dependent antibody of C03H-BH076N17/C03L-KT0 comprising a heavy chain variable region of SEQ ID NO:54 and a light chain variable region of SEQ ID NO:55 was identified, which bound hIL-6R in the presence of increasing concentration of MTA, but not adenosine, in Fig. 7. The antibody required about 30 µM MTA to begin to bind its target over background levels. This contrasts with Mia-PaCa2 tumors which were shown to have less than 0.1 µM MTA present in the tumor.
Example 4-2 and 6-7-5 taught MTA-dependent antibodies that target hIL-6R, hIL-6 and hIgA (page 245, paragraph 537, page 247, paragraph 543, and page 280, paragraph 623-624),
Different antibody libraries were used to obtain MTA-dependent antibodies.
S02 library
Table 14 on page 247 taught after several rounds of panning to identify clones with MTA-dependent binding there is a variable number of clones that bind to the antigen in an MTA or MTA and adenosine specific manner from the S02 library.
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275
684
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Antibody sequences of specific clones are taught in Table 15 on page 249.
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97
970
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Greyscale
While dissociation constants are taught in Table 16 on page 250
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183
496
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Greyscale
M30 library
Table 31 on pages 280-281 taught after several rounds of panning to identify clones with MTA-dependent binding there is a variable number of clones that bind to the antigen in an MTA or MTA and adenosine specific manner from the M30 library.
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184
676
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49
676
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Table 31 shows that a large majority of the antibody clones for hIL-6 and hIgA were unsuccessful at binding an antigen in an MTA specific manner. Thus, the generation of a successful antibody that is MTA-dependent is unpredictable.
Antibody sequences of specific clones are taught in Table 15 on page 249.
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media_image2.png
97
970
media_image2.png
Greyscale
While dissociation constants are taught in Table 16 on page 250
PNG
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183
496
media_image3.png
Greyscale
Instant Figs 28-30 taught that the hIL-6R antibody is MTA dependent and can target a bispecific hIL-6R-CD3 antibody to T cells to activate the T cells in the presence of exogenous MTA, wherein the concentrations were 300 µM MTA (Fig 28) and 10-100 µM MTA (Fig 29-30).
It is unknown if the MTA-dependent antibodies can effectively bind their targets to produce phenotypic effects at physiologically relevant concentrations of MTA.
Accordingly, Applicant has demonstrated that antibodies that bind to three possible protein antigens of interest in the presence of MTA "switches" that the art had reported occurred at higher levels in tumor tissue could be isolated from antibody libraries using Applicant’s selection technique.
Here, the art did not recognize, and Applicant has not described, a full structure shared by the claimed antigen-binding molecules whose antigen-binding activity changes in a 5'-methylthioadenosine (MTA)-dependent manner as broadly claimed that would correlate with the functional properties recited and allow binding to any protein target. The structure of an antibody does not allow one of skill in the art to immediately envision which members of the genus of antibodies would have the claimed functional MTA dependent activities and which would not for framework and CDRs residues. Accordingly, Applicant has not provided a sufficient structure/function correlation to adequately describe the invention as broadly claimed.
It is acknowledged that Applicant has provided several species falling within the claimed genus. The antibodies described were shown to have the function of binding one of three protein antigens, IL-6, IL-6R, and HSA, in the presence of the small molecule “switch” MTA. The claims, in contrast, encompass antibodies that bind any antigen and whose binding is dependent upon MTA with a variable CDR and any framework. Therefore, the claims encompass highly diverse species of antigen-binding molecules and the species described, limited to antibodies that bind three protein antigens, cannot be considered representative of the genus.
For these reasons, the claimed subject matter does not provide an enablement of the genus as broadly claimed.
Conclusion
Claims 18-46 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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