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 amendments and remarks filed 2-10-26 are acknowledged. Because the previous claims which were subject to an election of species requirement were canceled and replaced with new claims drawn to a since species of anti-CD3 antibody the election of species requirement set forth 12-10-25 has been rendered moot.
Claims 28-47 are pending and under examination.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 28-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 19, 22 and 23 of copending Application No. 18712739 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claim anticipates the instant claims.
Reference claim 11 (which is dependent on reference claim 1 drawn to anti-Id antibodies) encompasses in its breadth bispecific antibodies having a first binding domain having Vh and VL domains that bind to an antibody idiotype (anti-idiotypic antibodies), said Vh and VL domains being joined to heavy and light chain constant domains (see parts (i)-(iii) of reference claim 11-), and a second binding domain that binds to CD3, wherein said second binding domain has a Vh of SEQ ID NO: 260 and a Vl of SEQ ID NOs: 315, 325, 345, 445 or 455 (see part (vii) of reference claim 11-). More particularly, Section (vii) of reference claim 11 specifies the antibody may further comprise the heavy and light chain variable domains of SEQ ID NO: 260 (Vh) and any one of SEQ ID NOs: 315, 325, 345, 445 and 455 (VLs). Said reference SEQ ID NOs: are identical to SEQ ID NOs: 5234 and 5242 of the instant claims as shown below:
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Moreover, reference 19, 22 and 23, which are dependent on reference claim 11, further specify that in the instance that the antibody of reference claim 11(xi) which is “a multispecific antibody or antibody fragment,” the antibody can bind to any one of many additional antigens (reference claim 19), that the multispecific of claim 11(xi) can comprise various antibody fragments such as Fab or scFv (reference claim 22) and that the antibody of claim 11 can bind various idiotypic targets (reference claim 23).
Thus, the reference claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 46 and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer or a tumor in a human in need of such treatment, the method comprising administering to the cancer or tumor patient a therapeutically effective amount of a bispecific or multispecific antibody comprising (i) a CD3-binding site comprising the antibody or antibody fragment of claim 28 / claim 31, and (ii) a tumor-associated antigen binding site, wherein administration of said bispecific or multispecific antibody treats the cancer or tumor, does not reasonable provide enablement for treating cancer in any mammal in need of treatment comprising administering to the mammal an anti-CD3 antibody or antibody fragment according claim 28, including with, e.g., a monospecific anti-CD3 antibody or antibody fragment according claim 28, or for treating any disorder in any mammal in need of treatment, including, e.g., treating any infectious disease, the method comprising administering to the mammal an anti-CD3 antibody or antibody fragment according claim 28, including, e.g., a bispecific antibody having the variable domains of claim 28 and further having binding domains that recognize an antigen associated with any infectious disease.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As a preliminary matter, it is noted that specification working Example 1 describes the production of murine antibodies by immunization with cells that express either human or cynomolgus CD3. Example 2 describes a method of generating variants of the “SP34” anti-CD3 antibody, which was well-known in the prior art to bind an N-terminal epitope comprising “DGNE” residues of human CD3ε. At Table 2 the specification shows the claimed antibody binds with high affinity to human and cynomolgus CD3ε. Nowhere does the specification disclose or provide any guidance that the claimed anti-CD3 antibody can bind CD3ε expressed by any mammal, including murine CD3ε or any other CD3ε expressed by a non-human or non-cynomolgus mammal. Indeed, given the lack of homology between human CD3ε and more distantly related mammals such as mouse and sheep (see Sun et al., Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16867-72, at Fig. 1, cited herewith) the ordinarily skilled artisan would not
understand how to treat a disorder in any mammal, i.e., any mouse, any sheep, etc., using an antibody that was either selected for its binding to a cell expressing human CD3 or the highly homologous cynomolgus CD3, or that was derived from the “SP34” antibody, which itself was only known to bind to an N-terminal epitope of human and cynomolgus CD3 comprising the sequence DGNE which is absent from the N-terminus of the mouse and sheep CD3ε (see ibid).
At paras [0007] [0009] and [0010], the specification teaches:
“[0007] The TcR confers antigen specificity and the CD3 structures transduce activation signals to T cells. The CD3 complex contains four subunits. They can contain two zeta subunits, one epsilon subunit and either a gamma or a delta subunit. Antigen binding leads to the cross-linking and activation of the TCR complex. T-cell receptor signaling leads to T-cell activation and IL-2 production and other cytokines in a complex process….
[0009] Activation of the cytotoxic T cell may occur via direct binding of the CD3 antigen without the recognition of the MHC-peptide complex by the TcR. This alternative activation route can be achieved with anti-CD3 antibodies. Non-human monoclonal antibodies have been developed against some of the CD3 chains (subunits), as exemplified by the murine antibodies OKT3, SP34, UCHT1 or 64.1. (See e.g., June, et al., J. Immunol. 136:3945-3952 (1986); Yang, et al., J. Immunol. 137:1097-1100 (1986); and Hayward, et al., Immunol. 64:87-92 (1988)). Other CD3 antibodies are disclosed, for example, in U.S. Pat. Nos. 5,585,097; 5,929,212; 5,968,509; 6,706,265; 6,750,325; 7,381,803; 7,728,114. Bispecific antibodies with CD3 binding specificity are disclosed, for example, in U.S. Pat. Nos. 7,262,276; 7,635,472; and 7,862,813.
[0010] Many of these anti-CD3 antibodies bind the epsilon chain which leads to the development of highly activated T cells. Cancer immunotherapy with ordinary monoclonal antibodies does not typically activate T-lymphocytes sufficiently so as to elicit meaningful, targeted, pharmacologic activity towards the target cell type or tissue”
Paragraph [0262] of the specification instructs: “As disclosed herein and throughout, the inventive CD3 binding domains and antibodies comprising them may comprise monospecific, bispecific, or multispecific antibodies….”
Thus, the claimed methods given their broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art encompass in their breadth:
(i) the treatment of, e.g., cancer, by administering the anti-CD3 antibody of claim 28 / claim 31, even including by administering a monospecific anti-CD3 antibody (which is encompassed in the breadth of claims 28/31), and
(ii) treating various non-cancer conditions with an antibody that is bispecific for CD3 and for an antigen associated with, e.g., by an infectious disease.
With respect to (i), a publication of relevance to the claimed method of treatment is the work of Richards et al. (CANCER RESEARCH 59, 2096–2101, May 1, 1999, cited herewith) which describes an attempt to treat cancer by administering a “mitogenic” anti-CD3 antibody:
“Together the evidence strongly suggests that in vivo T-cell activation occurs after the administration of hOKT3γ4. Fever response, peripheral blood lymphocyte depletion, and increased CD25 expression suggest that the two highest dose levels tested (800 and 1600 mg) produce the greatest T-cell activation. Soluble products of T-cell activation (sIL-2R and IL-6) suggest that an hOKT3γ4 dose of 1600 mg produces the greatest T-cell activation, but this dose exceeds the maximally tolerated dose identified in this trial and cannot be recommended for further evaluation. Rather, the 800-mg dose of hOKT3γ4 can be safely administered on the schedule tested while providing measurable T-cell activation, which is comparable to the 1600-mg dose.” (see page 2101, 1st full paragraph). Despite the ability of an 800-mg dose of this hOKT3γ4 anti-CD3 antibody to be safely administered, and despite the teachings of Richards that “[m]alignant ascites resolved in three patients, one each with peritoneal mesothelioma, pancreatic adenocarcinoma, and ovarian adenocarcinoma,” (see abstract), Richards concludes “…it should be noted that there was no obvious correlation between the treatment dose and clinical effects observed. Whether hOKT3g4 has a particular role in the treatment of ascites or i.p. disease of any histology should be explored in future trials”
Similar to the teachings of Richards, Borrione (Leuk Lymphoma. 1996 Apr;21(3-4):325-30, cited herewith) likewise was unable to demonstrate treatment of cancer via a method wherein the T-cell activating anti-CD3 antibody OKT3 followed by continuous infusion of IL-2 was administered to a variety of cancer patients (2 multiple myeloma (MM), 1 B-cell lymphoma (NHL), 1 metastatic melanoma (ME)):
“The treatment did not revert tumor progression in the 2 patients with progressive disease (NHL, ME) and had only minimal effects in the 2 MM patients with stable disease. These data indicate that the sequential administration of OKT3 and IL-2 had no anti-tumor activity in this small series of patients with advanced cancer who were selected for treatment because of an increased number of HLA-DR+ T cells in the peripheral blood.” (see abstract)
A reason that CD3-binding antibodies have uncertain effects in vivo is because they would be expected by the skilled artisan to nonspecifically act on all subtypes of T cells. For example, anti-CD3 antibodies have the potential to act on pro-inflammatory as well as anti-inflammatory T cells, and also target activated and non-activated T cells (see Bardal et al., Applied Pharmacology, Chapter 17 - Immune Modifiers, W.B. Saunders, 2011, pages 215-232, cited herewith, at page 220, right col.).
Indeed, in was generally appreciated prior to applicant’s earliest filing date that in order for a CD3-binding, T-cell activating antibody to be useful in the treatment of cancer it must have a way of re-directing CD3-expressing T-cells to bind to and cytotoxically lyse cancer cells as opposed to non-specifically binding all CD3-expressing T-cells, including CD3-expressing T-cells distal from the cancer cells.
One example of this phenomenon is supplied by the teachings of Borlak et al. (Oncotarget. 2016 May 10;7(19):28059-74, cited herewith) where, despite the absence of EpCAM expression by hepatocytes, administration of the bispecific anti-CD3 / anti-EpCAM antibody (catumaxomab) caused hepatotoxicity in a number of cancer patients, with one patient exhibiting acute liver failure: “Given that all T cells express CD3 an anti-CD3 activation of effector T cells by catumaxomab can be assumed leading to non-specific killing of hepatocytes. Moreover, variability of T-cell CD3 membrane expression influences the capacity for T cell activation and may determine the risk for hepatitis among individual patients [21]. Besides, catumaxomab functions in a non-MHC restricted manner. Therefore, the observed cytolytic hepatitis would not require hepatocytes to express EpCAM but involves the combined activity of cytokines, granzyme B and perforin.” (see page Abstract; page 28059-60 bridging paragraph; and page 28071, right col., last full paragraph).
In sum, in view of the quantity of experimentation necessary, the lack of 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 trial and error experimentation to practice the claimed invention.
Turning to (ii), even if the claimed methods of treatment were to specify, e.g., that the administered anti-CD3 antibody must be a bispecific or multispecific antibody comprising (i) a CD3-binding site comprising the antibody or antibody fragment of claim 28 / claim 31, and (ii) an infectious disease-associated antigen binding site, such a treatment method would not be enabled by the teachings of the instant specification in view of the lack of the knowledge in the prior art of treating infectious disease with such antibodies.
For example, while there was knowledge in the art prior to 5-8-17 as to how to make and productively use human T cells modified to express a ligand binding domain which binds to, e.g., an HIV virus antigen expressed on the surface of an HIV infected human cell, said ligand binding domain further comprising a T-cell signaling domain(s) (see Masiero et al., Gene Therapy (2005) 12, 299–310, cited herewith), the treatment of infectious disease with chimeric antigen receptor redirected T cells was still very undeveloped even 6 years later (see Mancini et al., Clin Microbiol Infect 2015; 21: 715–716, at page 715, right col., cited herewith).
Discovery of chimeric immunoreceptors which were capable of recognizing antigens on the surface of infected cells would have required far more than routine experimentation for several reasons. For example, as taught by Full et al. (JOURNAL OF VIROLOGY, Apr. 2010, p. 4083–4088, cited herewith), the viral antigen targeted by a chimeric antigen receptor (CAR) would need to be expressed on the target cell surface for sufficient periods of time during the viral infection to be suitable for recognition by the CAR expressing T-cell; the epitope recognized by the CAR would need to be conserved between various stains of the infectious agent to be of widespread practical use; and the viral antigen recognized by the CAR could not be one where soluble versions of said antigen out compete surface bound viral antigen for CAR binding (see page 4083, right col., 1st full paragraph – page 4085, left col.; page 4087, right col., last full paragraph). Similar concerns were also discussed by Masiero at page 302 col. bridging paragraph, at page 305, left col., 1st full paragraph; and at page 305 column bridging paragraph.
Note that while the teachings of Masiero and Full were concerned with the use of chimeric antigen receptor expressing T-cells for the treatment of HIV or CMV, the ordinarily skilled artisan contemplating the use of the claimed anti-CD3 antibodies to treat infectious disease would also face the same uncertainties with respect to choosing an appropriate infectious disease target antigen.
As another example of the knowledge in the prior art related to similar issues, consider the challenge that would have faced the skilled artisan interested in treating an Ebola virus infection by practicing the methods of claims 46 and 47. As described by Ito et al. (JOURNAL OF VIROLOGY, Feb. 2001, p. 1576–1580, cited herewith), Ebola virus infected cells were known to produce a secreted glycoprotein (SGP) which served as a decoy for absorbing neutralizing antibodies that would otherwise bind to the Ebola GP glycoprotein to control its ability to bind certain cell types, i.e., its cell tropism (see page 1576, first paragraph of the left col. and page 1579, col. bridging paragraph).
Likewise, as described by Hoenen et al. (Trends in Molecular Medicine, Volume 12, Issue 5,
2006, Pages 206-215, cited herewith), it was unclear to the ordinarily skilled artisan how successful passive immunization with sera obtained from previously infected Ebola patients would be in treating actively infected individuals (see page 212, right col., 1st full paragraph), much less which epitope(s) of Ebola GP, expressed on the surface of which cell(s), can be recognized, e.g., by a putative GP specific “ligand binding domain” in a way that would allow a hypothetical “infectious disease” directed bispecific anti-CD3 binding antibody to bind and kill the Ebola infected cell.
By contrast, the instant specification gives no guidance as to how to make ligand binding domains capable of specifically recognizing and killing cells infected with the broad genus of infectious agents encompassed in the breadth of the instant claims.
In sum, 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 trial and error experimentation to practice the claimed invention.
No claims are allowed. However, claims 38-45 are not rejected but are instead objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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
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