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 .
Claims 1-3 are pending and under examination.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 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.
The instant specification teaches the treatment of cancer by “adoptive immunotherapy” wherein the autologous lymphocytes from a cancer patient are expanded in vitro by exposure to cancer cell lysate and then re-administered to said cancer patient (see page 2, 1st full paragraph); where administration of an anti-CD3 antibody can “attract T cells through specific binding with CD3….the attracted T cells may induce immune responses in the vicinity thereof, and may further attack tumors such as cancer cells….” (page 5-6 bridging paragraph); the production of an anti-CD3 antibody-drug conjugate (ADC) (see page 7, 2nd full paragraph); an embodiment wherein “the antibody may also be used as a chimeric antigen receptor (CAR)-based therapeutic agent containing the same. Examples of such a therapeutic agent preferably include, but are not limited to, chimeric antigen receptor T cell (CAR-T cell) or chimeric antigen receptor natural killer cell (CAR-NK cell) therapeutics….” (see page 8, 4th full paragraph); an embodiment wherein “[t]he antibody may also be used in the form of a bispecific antibody containing an anti-CD3 antibody. The bispecific antibody is an antibody that has capacity of binding to two antigens at the same time, and may typically exist in a form in which heavy and light chain pairs that bind to different antigens are linked to each other….” (see page 8, last full paragraph); including a bispecific anti-CD3 antibody which binds to an “immunopotent cell-specific target molecule,” as set forth at page 9, 1st full paragraph “The bispecific antibody may exist in a form in which the anti-CD3 antibody is bound to an antibody or a fragment thereof having binding capacity to an immunopotent cell-specific target molecule. The immunopotent cell-specific target molecule may preferably be selected from, but is not limited to, TCR/CD3, CD16 (FcyRIIIa), CD44, CD56, CD69, CD64 (FcyRI), CD89, and CD11b/CD18 (CR3).”
However, the instant specification provides insufficient direction or guidance to use the claimed antibodies for the treatment of cancer.
One 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 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.
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