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 .
Applicant’s 11-21-25 election of various species of invention, without traverse, is acknowledged.
Upon reconsideration, the species of method wherein (i) first and second antigen-binding molecules will be administered will be examined along with (ii) the elected species of method wherein a first antigen-binding molecule but not a second antigen-binding molecule is administered. Moreover, since claim 43 is generic to each of (i) and (ii) above said election of species requirement has been withdrawn.
Claims 21-31, 43-48, 50 and 53-56 are pending and under examination as they read on the species of method wherein the first antigen-binding domain is “a TNFR superfamily-binding domain,” wherein the sub-species of TNFR superfamily-binding domain is “an anti-CD137 antibody,” and wherein the T cell receptor complex-binding domain is “a CD3-binding domain.”
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 21-23, 26-31, 43-45, 48, 50, 53 and 54 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Lacher (WO2014165818A2, of record).
Lacher teaches the treatment of a subject having prostate cancer by administering a combination of bispecific binding reagents, wherein said binding reagents provide both stimulation and co-stimulation of immune cells against prostate cancer (see paragraph 118).
In the instance where two bispecific binding reagents are so provided this is referred to as “Dual Stimulation of T cell technology” or “DuST” (see ibid, paragraph 144; Figure 4). As illustrated in Fig. 4B, the principal of DuST is that combined stimulation of immune cells with, e.g., a bispecific antibody that binds a target TAA #1 and CD3, and co-stimulation of these same immune cells with, e.g., a bispecific antibody that binds a target TAA #2 and CD28, leads to target cell death.
Lacher further teaches their bispecific binding reagents bind to the target immune cell by specifically binding, e.g., CD3 epsilon or CD137, and further binding to one or more prostate tumor-associated antigen (TAAs) such as STEAP1 and/or EpCAM (see paragraphs 6, 19, 97, 100, 134, 135, Example 1 and claims 18, 19, 21 and 74-76).
At claim 77 which depends from the methods of treatment of claims 74-76, Lacher teaches “the method further comprises simultaneously or sequentially administering a second bispecific binding reagent, wherein the second bispecific binding reagent specifically binds at least one antigen that is not specifically recognized by the first bispecific binding reagent.”
Lacher further teaches that their bispecific binding reagents are designed to avoid widespread/systemic T cell activation due to their monomeric form which helps to ensure T cell activation is linked to the presence of target cells (see paragraphs 89-91).
Thus, the teachings of Lacher anticipate the methods of claims 21-23, 26-31, 43-45, 48, 50, 53 and 54.
Note that insofar as applicant may attempt to assert that Lacher does not explicitly teach that their method of treating prostate cancer induces cytotoxicity, given that the Lacher teaches the treatment of prostate cancer by administering first and second antigen-binding molecules as recited for example in claim 21, the method will necessarily induce cytotoxicity since the outcome of “Dual Stimulation of T cell technology” or “DuST” is cancer cell death, a.k.a. “cytotoxicity” as illustrated in Fig. 4B.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 21-31, 43-48, 50, and 53-56 are rejected under 35 U.S.C. 103 as being unpatentable over Lacher (WO2014165818A2) as applied to claims 21-23, 26-31, 43-45, 48, 50, 53 and 54 above, and further in view of Nezu et al. (WO2012073985, which is the Japanese language equivalent of US20140112914, which, because it is published in English, will be used for reference to the ‘818) and Guo et al. (6805869) as evidenced by Melero et al., Clin Cancer Res; 19(5); 1044–53. (2013), Palazon et al. (Cancer Discov; 2(7); 608–23. (2012)), Chen et al. (20150166661), Van Den Brink et al. (20160333095)(all of record), and Klein et al. (20170349666, cited herewith).
As set forth above, Lacher teaches the treatment of a subject having prostate cancer by administering a combination of bispecific binding reagents, wherein said binding reagents provide both stimulation and co-stimulation of immune cells against prostate cancer (see paragraph 118).
In the instance where two bispecific binding reagents are so provided this is referred to as “Dual Stimulation of T cell technology” or “DuST” (see ibid, paragraph 144; Figure 4). As illustrated in Fig. 4B, the principal of DuST is that combined stimulation of immune cells with, e.g., a bispecific antibody that binds a target TAA #1 and CD3, and co-stimulation of these same immune cells with, e.g., a bispecific antibody that binds a target TAA #2 and CD28, leads to target cell death.
Lacher further teaches their bispecific binding reagents can bind to the target immune cell by specifically binding, e.g., CD3 epsilon and CD137, and further binding to one or more prostate tumor-associated antigen (TAAs), such as STEAP1 and/or EpCAM (see paragraphs 6, 19, 97, 100, 134, 135, Example 1 and claims 18, 19, 21 and 74-76).
At claim 77, which depends from the methods of treatment of claims 74-76, Lacher teaches “the method further comprises simultaneously or sequentially administering a second bispecific binding reagent, wherein the second bispecific binding reagent specifically binds at least one antigen that is not specifically recognized by the first bispecific binding reagent.”
Lacher further teaches that their bispecific binding reagents are designed to avoid widespread/systemic T cell activation due to their monomeric form which helps to ensure T cell activation is linked to the presence of target cells (see paragraphs 89-91).
However, Lacher does not explicitly teach a method for inducing cytotoxicity, suppressing cell proliferation, activating immunity, or treating or preventing cancer, said method comprising administering to a subject in need thereof, a first antigen-binding molecule that comprises:
(1) a cancer-specific antigen-binding domain and tumor necrosis factor (TNF) receptor superfamily-binding domain, and
(2) a second antigen-binding molecule that comprises a cancer-specific antigen-binding domain and a T cell receptor complex-binding domain,
wherein the first antigen-binding molecule or the second antigen-binding molecule is an antigen-binding molecule that further comprises an FcRn-binding domain (see, e.g., claim 24), including wherein said FcRn-binding domain is a variant antibody Fc region having decreased Fcγ receptor-binding activity compared to the corresponding native Fc region (see, e.g., claim 25); more specifically, wherein said FcRn-binding domain variant is a variant IgG1 Fc region comprising an alanine amino acid substitution at position 256 (see, e.g., claim 55).
That said, as described by Nezu, and as well appreciated in the art, the scFv based bispecific antibodies featured by Lacker, while effective, are inconvenient and unsafe for patients due to their short serum half-life and need to be administered by continuous infusion using a minipump (see, e.g., Nezu paragraph 8). As further described by Nezu, while full length bi-specific antibodies comprising an Fc region do not suffer from the same short serum half-life as the scFv-based bispecific antibodies of Lacker, such antibodies have a different drawback in that they can bind both T cells and other immune effector cells such as NK cells and macrophage via the Fc region, i.e., in a cancer antigen-independent manner that does not depend on their cancer antigen binding specificity, which causes toxicity in the patient due to cytokine storm-like side effects (see, e.g., paragraphs 2 and 7).
However, Nezu describes bispecific antibody-based molecules that solve each of the difficulties mentioned above. In particular, Nezu teaches bispecific antibodies wherein the Fc region has been mutagenized to reduce FcγR binding (see, e.g., paragraphs 164-195), including in a preferred embodiment substitution of the amino acid at position 265 with a alanine (see paragraph 182). It would have been obvious to one of ordinary skill in the art as of applicant’s first filing date that said antibodies have the advantage of longer serum half-life without the disadvantage of cancer antigen-independent triggering of cytokine release.
Nezu further describes two substantially similar versions of a particular TAA(GPC3) x CD3 bispecific antibody having reduced FcγR-binding activity, wherein testing of one of said antibodies demonstrated it to have potent target cell killing activity in vivo (see Example 7 and Figs. 19 and 21). Note in this regard that glypican-3 is expressed by a variety of cancer types including, e.g., hepatocellular carcinoma and prostate cancer (see para 286).
It would have been obvious to one of ordinary skill in the art planning to practice the “DuST” method of Lacher to promote cancer cell death via combined stimulation and co-stimulation of immune cells that it would be advantageous to substitute, e.g., the glypican-3 x CD3 bispecific antibody of Nezu Example 7 for the BiTE-like, tumor-associated antigen x CD3-binding molecule of Lacher since the bispecific antibody of Nezu would have been known to have a substantially longer serum half-life.
Turning to the co-stimulatory agent of the DuST method of Lacher, in 1998 Guo filed a patent application describing "bridge molecules" (also referred to as “Bi-MAbs” by Guo) which bring two or more cells together by attaching to the cells with their binding sites. In particular, Guo instructs: “[p]referably, a bridge molecule can bring an autologous target diseased cell together with an effector cell and deliver a signal to the effector cell to activate or enhance the effector cell's immune response against the target. A bridge molecule has one or more binding sites for stimulatory and/or costimulatory molecules on the effector cells. These binding sites can be designed to activate a positive regulator of T cell activation (e.g., CD28, 4-lBB)….A bridge molecule may also have one or more binding sites for antigens on the surface of the target diseased cell. Bridge molecules include, but are not limited to, bispecific monoclonal antibodies, fusion proteins….” (see Col. 5, line 18 – 35). With respect to the bridge molecule binding sites, Guo re-emphasizes that CD28 and 4-1BB are preferred ligands for the costimulatory binding site (see col. 6, lines 15-17) and teaches targeting specific antigens on the diseased cell, preferably unique antigens when the bridging molecule is to be used in vivo (see col. 12, lines 44-49). With respect to the later, Guo further teaches a method of treating a tumor by injecting the Bi-MAbs into a subject in need thereof (see col. 12-13 bridging paragraph – col. 13, line 29). In one particular embodiment Guo teaches administering the Bi-MAbs directly into the tumor cells via guided fine needle injection where “…the Bi-MAbs or other bridge molecules bind to an antigen present on the target diseased cells but not present on normal tissues at the disease location so as to avoid generating immune response against healthy cells. In another preferred embodiment, the Bi-MAbs or other bridge molecules bind to an antigen unique to the target diseased cells.” (see Example 14 including at Col. 31, lines 59-65).
Guo teaches that the bridging molecule can be prepared, e.g., by chemically recombining individual monoclonal anti-diseased cell antigen and anti-costimulatory Mabs into bispecific constructs having a heavy and light chain pair, i.e., having a Fab that binds the diseased cell antigen and having a second heavy and light chain pair, i.e., having a second Fab that binds the costimulatory molecule (see col. 14, lines 23-33 and Example 2).
According to Guo, binding of tumor cells with a Bi-MAb comprising a single cancer specific antigen binding Fab and a single CD137 binding Fab renders said tumor cells immunogenic in an in vivo animal model system, i.e., renders said tumor cell susceptible to the animal’s immune response thereby immunizing against subsequent challenge with tumor cells (see Example 8 in Tables II and III). Thus, as would be readily apparent to the skilled artisan, bispecific TAA x CD137 antibodies have their expected immune stimulatory activity in vivo.
Thus, while Guo does not appear to have contemplated diminishing cancer antigen-independent triggering of cytokine release by introducing mutations that reduce FcγR-binding into the antibody Fc domains, the teachings of Guo demonstrate the knowledge in the art that full-length, bispecific TAA x CD137 antibodies have their expected immune stimulatory activity in vivo.
Given the dual stimulation of T cell (DuST) method for the treatment of cancer described by Lacher relies on a co-stimulatory agent which the ordinarily skilled artisan would recognize as clearly suffering from the short serum half-life of a non-Fc-containing bispecific, it would have been obvious to the ordinarily skilled artisan that the co-stimulation agonist to be used in the DuST method could be improved if this agent were to include an Fc domain capable of extending serum half-life while being incapable of binding FcγR.
Thus, the ordinarily skilled artisan would have been motivated to apply the teachings of Nezu to the full-length, bispecific TAA x CD137 antibodies of Guo, and in so doing modify the Fc domain of the bispecific TAA x CD137 antibody of Guo to reduce FcγR-binding, thereby yielding a bispecific TAA x CD137 antibody which avoids the cancer antigen-independent, but Fc domain dependent, triggering of cytokine release by CD137-expressing T-cells and NK cells, while having a serum half-life longer than the short serum half-life antibodies of Lacher.
In summary, given the obvious advantages of bispecific anti-TAA x anti-CD137, such as an anti-EpCAM x anti-CD137, and anti-glypican-3 x anti-CD3 antibodies, each having Fc domains mutated so as to reduce FcγR-binding and in turn mitigate antigen-independent, Fc-dependent toxicity, for practicing the DuST method of Lacher, it in turn would have been obvious to one of ordinary skill in the art to administer said FcRn-binding antibodies with diminished Fcγ receptor binding activity for the treatment of, e.g., prostate cancer.
Notably in this regard, the skilled artisan would have reason to be just as concerned with FcγR-binding induced anti-CD137 activation of T-cells as they would with FcγR-binding induced anti-CD3 activation of T cells. In fact, there was a known propensity of conventional FcγR-binding, agonistic anti-CD137 antibodies to trigger T-cell liver infiltration and hepatitis as evidenced by Melero at page 1048, right col., 1st full paragraph – page bridging paragraph. Along these same lines, prior art efforts had been made to locally inject agonistic anti-CD137 antibody at the tumor site so as to limit spreading to other parts of the body where the antibody could cause off-target toxicity as evidenced by Palazon at page 610, left col., 1st and 2nd full paragraph; at page 616, right col. 2nd and 3rd paragraphs.
Likewise, it would be well understood by the skilled artisan that bispecific antibodies having reduced FcγR-effector function depend upon tumor-associated antigen binding to induce CD3- or CD137-crosslinking, and, in turn signal transduction. Such a notion is reflected in the general knowledge in the art as evidenced by the teachings of Nezu at paragraphs 2-8, 24, 29 and Example 3; Van Den Brink at paragraphs 4, 5, 248-250 and Chen at paragraphs 1402, 1419 – 1421. Thus, the ordinarily skilled artisan was well aware that the FcγR-binding activity of bispecific glypican-3 x CD3-binding, as well as TAA x CD137-binding antibodies, e.g., bispecific EpCAM x CD137 binding antibodies, can be diminished while retaining effective tumor target cell-dependent T-cell activation. In so doing, it would have been obvious to the ordinarily skilled artisan that they could minimize cancer antigen-independent (but Fc domain dependent) release of cytokines by CD3- and CD137-expressing cells, such as T-cells and/or NK-cells.
Given the reference teachings and the general knowledge in the art, it would have been obvious to the ordinarily skilled artisan wishing to treat cancer, e.g., prostate cancer, via a method wherein “DuST” agents were used to stimulate / co-stimulate T cells in the presence of a tumor-associated antigen expressing cancer target (consistent with the teachings of Lacher), that
said “DuST” agents could be anti-TAA x CD3-binding and anti-TAA x CD137-binding antibodies, each of said antibodies modified to reduce FcγR-binding, thereby yielding bispecific antibodies which avoid the cancer antigen-independent, but Fc domain dependent, triggering of cytokine release by CD3 and/or CD137-expressing T-cells and NK cells, while having the obvious advantages of a serum half-life longer than the short serum half-life antibodies of Lacher. An additional reason that the skilled artisan would have been motivated to treat cancer by the method described above was because it was known in the art that T cell activating bispecific antigen binding molecules (TCBs) having a tumor associated antigen binding domain, such as a FolR1-binding domain, and further having a CD3-binding domain (“FolR1-TCB”), induced the expression of CD137 by CD8+ T cells (see Klein at paras 143, 751 and Fig. 40B), consistent with well-known in the prior art role of CD137 in co-stimulation of primary TCR activation.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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 21-31, 43-48, 50 and 53-56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The considerations that are made in determining whether a claimed invention is supported by an adequate written description are outlined in the MPEP, for example at § 2163 (emphasis added):
“3. Determine Whether There is Sufficient Written Description to Inform a Skilled Artisan That Inventor was in Possession of the Claimed Invention as a Whole at the Time the Application Was Filed
ii) For each claim drawn to a genus:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)….”
So, in effect, since it need not have any particular structure the claimed genus as a whole is only described as having the ability to specifically bind to a target.
Applicant is reminded that “…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").” (MPEP § 2163(II)(A)(3)(a)).
In the instant specification, there is no language that adequately describes with the requisite clarity and particularity the claimed genus of antigen-binding molecules comprising: (1) a cancer-specific antigen-binding domain; and (2) a tumor necrosis factor (TNF) superfamily-binding domain or a TNF receptor superfamily-binding domain and further comprising: (1) a cancer-specific antigen-binding domain; and (2) a T cell receptor complex-binding domain, even when said molecule are further limited to those molecules wherein the TNF receptor superfamily binding domain aspect “is a CD137-binding domain,” or wherein either of the aforementioned molecules “is a bispecific antibody.” A description of what a material does, rather than of what it is, does not suffice to describe the claimed invention.
While the written description requirement can by satisfied without an actual reduction to practice, the disclosure of a catalog of potentially effective substances (i.e., proteins, polypeptides, oligopeptides, or peptides) that might be found to be useful in practicing the claimed invention does not fulfill the written description requirement.
The Federal Circuit has decided that a generic statement that defines a genus of substances primarily by their functional activity, e.g., by their ability to perform cancer-specific antigen binding, or TNF superfamily binding, or TNF receptor superfamily binding, or TCR complex binding, does not provide an adequate written description of the genus. Further specifying that the antigen binding molecules comprise an FcRn-binding domain, or are a “bispecific antibody,” likewise does not meaningfully put the skilled artisan in possession of the breadth of antigen binding molecules encompassed by the instant claims because any member of the potentially vast genus of any protein, polypeptide, oligopeptide, or peptide having the claimed binding ability can be fused to an Fc domain or to a an antibody or antigen-binding fragment thereof to produce a molecule which is an FcRn-binding domain or a “bispecific antibody.”
The skilled artisan merely informed that a given protein, polypeptide, oligopeptide, or peptide has the ability to perform cancer-specific antigen binding, or TNF receptor superfamily binding, or TCR complex binding would have no idea what structure such a molecule would or could take.
In The Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997) the Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure, formula, chemical name, or physical properties of those members, rather than by merely reciting a wish for, or even a plan for obtaining a genus of molecules having a particular functional property. The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of genus must be capable of doing, not of the substance and structure of the members.
In this instance, because the claimed antigen-binding molecules do not need to have any particular structure or share any particularly identifying structure features which correlate with their claimed binding abilities, it is submitted that the skilled artisan could not envisage representative members of the claimed genus. Accordingly the specification would not reasonably convey to the skilled artisan applicant's possession of the claimed invention as of the filing date of the application, so as to satisfy the written description requirement set forth under 35 U.S.C. § 112, first paragraph.
Adding here to the reasons that the specification would not reasonably convey to the skilled artisan applicant's possession of the claimed invention as of the filing date of the application, absent the adequate description of a representative number of members of the genus of antigen binding domains to which the claims are directed, the supporting disclosure amounts to no more than a mere invitation to identify a protein, polypeptide, oligopeptide, or peptide having the claimed binding activity which can be used in producing the claimed antigen-binding molecules.
Furthermore, it is aptly noted that the Federal Circuit has stated that a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. See Noelle v. Lederman, 69 USPQ2d 1508 1514 (CA FC 2004) (citing Enzo Biochem II, 323 F.3d at 965; Regents, 119 F.3d at 1568).
The skilled artisan cannot predict whether any given protein, polypeptide, oligopeptide, or peptide will possesses the ability to perform cancer-specific antigen binding, or TNF receptor superfamily binding, or TCR complex binding. Rather the ability of a protein, polypeptide, oligopeptide, or peptide to specifically bind to any given function must be determined empirically.
Notably, in the Ex Parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007) precedential decision the Board found a disclosure insufficient to satisfy the written description requirement, and at page 1417 noted the following:
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”.
The specification does not reasonably convey to the skilled artisan applicant's possession of the claimed invention as of the filing date of the application, so as to satisfy the written description requirement set forth under 35 U.S.C. § 112, first paragraph.
Claims 21-31, 43-48, 50 and 53-56 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.
M.P.E.P. § 2164.01 states:
“…The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. See also In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term ‘undue experimentation,’ it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. See MPEP § 2164.06 for discussion of quantity of experimentation, including determining reasonableness of experimentation. See also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) (‘The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation.’).).”
Likewise consistent with the guidance set forth in MPEP § 2161.01(a) regarding “Undue Experimentation Factors,” the amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not have been sufficient to have enabled the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue and/or unreasonable experimentation.
The reasons it is submitted that the specification would not reasonably enable the skilled artisan to practice the claimed methods without undue and/or unreasonable experimentation are related to the reasons the claims have been rejected as failing to satisfy the written description requirement above. Any method that relies on products that have not been adequately described with the requisite clarity and particularity to permit the skilled artisan to make, or make and use said products in such a method cannot be made or used without undue and/or unreasonable experimentation.
Apart from exemplifying the production of particular bispecific antibodies wherein one heavy and light chain arm binds the tumor associated antigen GPC3, and the second heavy and light chain arm binds CD137, or wherein one heavy and light chain arm binds the tumor associated antigen GPC3, and the second heavy and light chain arm binds OX40, the instant specification provides insufficient direction or guidance as to using the vast breadth of any TNF receptor superfamily-binding domain1 to make antigen-binding constructs with relevance to the treatment of cancer.
The skilled artisan recognizes that there is a level of uncertainty and unpredictability associated with attempting to make and use an antigen-binding domain in a method of treating cancer wherein the cancer targeting domain is potentially fused to any TNF receptor superfamily-binding domain.
This is because, even as of applicant’s earliest filing date, while the skilled artisan understood the effect of stimulating, e.g., CD137, OX40 or GITR signaling, many of the other TNF receptor superfamily ligands were less well characterized and expected to be subject to multi-layered, complex regulatory factors:
“These families of receptor–ligand pairs are susceptible to multiple layers of regulation because of the following mechanistic facts:
The level of surface expression depends on the activation state of the lymphocyte: for the immunomodulatory mAb to be effective, expression of the target molecule on tumor-infiltrating lymphocytes or other antitumor T cells is critical.
Differential expression, distribution, and function on naïve versus memory T-cell subsets.
Differential recruitment to the cytoplasmic tail of members of the TNFR-associated factor (TRAF) family of signaling adaptors whose expression is also regulated upon activation.
The level of expression of the ligands is controlled by the activation/maturation state of the antigen presenting cells.
The existence and regulation of negative feedback mechanisms such as deubiquitinases and phosphatases that quench signals from the receptors.”
(see Melero et al., Clin Cancer Res; 19(5); 1044–53. (2013), of record, at Introduction on pages 1044-45; see also Table 1).
Likewise, the skilled artisan would have to resort to undue experimentation to begin discovering how to use the breadth of the claimed antigen-binding molecules in the context of method of treating cancer as it reads on binding to a cancer-specific antigen and any TNF receptor superfamily-binding member given the uncertain effects of such molecules on APC as illustrated by Melero Fig. 1.
Additionally, the skilled artisan would have to resort to undue experimentation to begin discovering how to use the breadth of the claimed antigen-binding molecules in the context of method of treating cancer as it reads on binding to a cancer-specific antigen and any “T cell cell receptor complex-binding domain” because as described by Reithmuller (Cancer Immun. 2012;12:12, cited herewith) while it was understood prior to applicant’s earliest filing date how the binding of a bispecific anti-CD3 x anti-tumor associated antigen (TAA) binding antibody could activate T-cells in the absence of a “second signal,” e.g., via CD28 or CD40 signaling, wherein the CD3-binding portion of the bispecific antibody acts by “…establishing contacts between effectors and targets…aggregating their engaged antigens on the two opposite cell membranes into a kind of microcluster or patch whereby the two CD3ε heterodimers come in close contact and, by induced conformational change, start the downstream signaling process through the transmembrane bundle of the TCR complex” (see page 3, right col., 3rd full paragraph), neither the instant specification nor the knowledge in the art provide sufficient direction or guidance to do the same with any a bispecific cancer-specific antigen binding domain x any T cell receptor complex binding domain.
For example, the “T cell receptor complex-binding domain” of the instant claims given its broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art encompasses in its breadth, e.g., molecules that bind to the CD4 adaptor. However, neither the instant specification nor the knowledge in the art provide sufficient direction or guidance for the skilled artisan to make a CD4 binding domain that can activate T-cells in a way that is the same as or equivalent to the mechanism by which a CD3xTAA bispecific antibody activate T-cells as described above.
Applicant is reminded that reasonable correlation must exist between the scope of the claims and scope of enablement set forth.
In deciding In re Fisher, 166 USPQ 18, 24 (CCPA 1970), the Court indicated the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. “Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC 1997).
Thus, the overly broad scope of the claims would merely serve as an invitation to one skilled in the art to begin identifying antigen-binding molecules with one arm the recognizes TNF superfamily-binding member(s), or TNF receptor superfamily-binding member(s) which might be useful in the setting of cancer; yet, defining a substance by its principal biological activity amounts to an alleged conception having no more specificity than that of a wish to know the identity of any material with that biological property. See Colbert v. Lofdahl, 21 USPQ2d 1068, 1071 (BPAI 1991).
Finally, with respect to practicing the method of claims 21, 48 and dependent claims thereof so as to successfully “prevent[] cancer,” the phrase “preventing cancer” is not defined by the instant specification; however, the plain meaning of this term is evident from the Webster's New World Dictionary which defines “prevent” as to make impossible by prior action and keep from happening (see Third College Edition, 1988, see page 1067, cited herewith). Thus, the instant claims given their broadest reasonable interpretation consistent with the instant specification and with the plain meaning of prevent / preventing read on a method whereby a patient can be prospectively treated prior to detection of cancer, and thereby avoid getting cancer. However, as has been long known in the art, the etiology of cancer is complicated and poorly understood, and as a consequence the skilled artisan is generally unable to say in advance, with any reasonable degree of certainty and precision, who will eventually develop any one or more of hundreds of different types of cancer falling into these vast genera. For example, it was known in the art that many potential factors were hypothesized to cause a person to be at risk of a brain tumor, only for subsequent work to show these putative factors to have no predictive value (see, e.g., McKinney, J Neurol Neurosurg Psychiatry 2004;75(Suppl II):ii12–ii17, at pages ii15-16, cited herewith). Thus, the skilled artisan would certainly not prospectively treat a patient for a potential brain cancer based on the presence of such uncertain factors. In view of the above, undue experimentation would be required to practice the invention commensurate with the breadth of the claims based on the disclosure of the instant specification and the knowledge in the prior art.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
In conclusion, upon careful consideration of the factors used to determine whether undue experimentation is required, in accordance with the Federal Circuit decision of In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988), the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to practice the claimed methods of treatments at the time the application was filed without undue and/or unreasonable experimentation.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
1 According to the instant specification at paragraph 60, “…factors belonging to the ‘TNF superfamily’ or the ‘TNF receptor superfamily’, ligands having a trimeric structure and receptors with a trimeric structure to which the ligands bind, which contribute to activation of various immune cells are known…Examples of factors belonging to the TNF superfamily or the TNF receptor superfamily include CD137, CD137L, CD40, CD40L, OX40, OX40L, CD27, CD70, HVEM, LIGHT, RANK, RANKL, CD30, CD153, GITR, and GITRL. Preferred factors include, for example, CD137 and CD40. A more preferred factor is, for example, CD137.”