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 remarks and amendment filed 9-10-25 is acknowledged.
Claims 83, 110-128 and 130 are pending and under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 130 stands 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 rheumatoid arthritis characterized by the presence of CD20 expressing B cells comprising parenterally administering to a human patient with rheumatoid arthritis a therapeutically effective amount of a bispecific antibody comprising (a)(i) and (a)(ii), and (b)(i) and (b)(ii) as recited in new claim 130, does not reasonably provide enablement for practicing the breadth of the claimed method of treatment which encompass treatment of a wide variety of specifically recited diseases which are “…characterized by the presence of CD20 expressing B cells…wherein the disease is psoriasis, psoriatic arthritis…,” or a variety of additional autoimmune and/or inflammatory diseases recited in claim 103, in the absence of undue trial and error experimentation.
As set forth in the prior Office Action at page 8-9 bridging paragraph through the 2nd full paragraph on page 9,
“…neither the instant specification nor the knowledge in the art provide sufficient direction or guidance as to which particular diseases contained within this extensive list immune of ‘disorders in which CD20 expressing B cells are involved’ are diseases where CD20-expressing cells, per se, are integral to the disease pathology in a way that depleting said CD20-expressing cells with the claimed antibody would be expected to treat said disease.
For example, with respect to treating lupus nephritis (LN) by administering a CD20+ B cell depleting antibody, Rovin et al. (ARTHRITIS & RHEUMATISM, Vol. 64, No. 4, April 2012, pp 1215–1226, cited herewith) taught the following: “EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab) study in patients with active extrarenal SLE receiving immunosuppressants and corticosteroids failed to demonstrate added benefit from rituximab (25), other studies have implicated B cells in the pathogenesis of LN (26), suggesting a role for rituximab in the treatment of LN (24,27,28).” (see page 1216, left col., 2nd paragraph). That said, the clinical trial of Rovin “failed to demonstrate the superiority of rituximab added to MMF plus corticosteroids over MMF plus corticosteroids alone in achieving either combined complete and partial responses or complete responses alone,” and “Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment.” (see final paragraph on page 1224 and Abstract, respectively).
Similarly, in the related diseases systemic lupus erythematosus (SLE), Merrill et al. (ARTHRITIS & RHEUMATISM , Vol. 62, No. 1, January 2010, pp 222–233, cited herewith) showed in a clinical trial that the rituximab anti-CD20 provided no benefit as compared to placebo, “No differences were noted between placebo and rituximab in the primary and secondary end points,” see Abstract, even though for most treated patients “Significant B cell depletion was obtained within 2 weeks of rituximab administration….” (see page 229, right col., 2nd paragraph).”
Moreover as further described at page 11, 1st full paragraph of the prior office action, “Likewise, the pleiotropic effect of depleting B-cells in EAE immunopathogenesis would have prompted substantial uncertainty in the ordinarily skilled artisan contemplating treatment of multiple sclerosis. As described throughout the Discussion of Matsushita et al. (J Clin Invest. 2008;118(10):3420-3430, cited herewith), any planned attempt to treat multiple sclerosis by depleting CD20 expressing cells would require a precise threading of the needle with respect to the timing of the treatment dose in particular patients in need thereof; indeed, an attempted treatment of multiple sclerosis by intrathecally administered rituximab was halted due to insufficient efficacy (see Komori et al., Annals of Clinical and Translational Neurology 2016; 3(3): 166–179, cited herewith).”
While applicant’s remarks of 9-10-25 at page 8, 2nd paragraph, that the now claimed species of diseases are those “in which CD20 expressing B cell are involved, including diseases in which autoantibodies and/or excessive B lymphocyte activity are prominent,” this assertion is not sufficient to address the teachings of the prior art set forth above that describe how, even when B-cells are implicated in pathogenesis, such an observation does not necessarily imply that depletion of CD20 expressing B cells will treat the disease, e.g., as was true for lupus nephritis, systemic lupus erythematosus and multiple sclerosis as set forth in the prior Office Action.
Moreover, additional species recited in new claim 130 “in which CD20 expressing B cell are involved, including diseases in which autoantibodies and/or excessive B lymphocyte activity are prominent” (from applicant’s remarks of 9-10-25 at page 8, 2nd paragraph) were shown in the prior art to not be treatable via depletion of CD20 expressing cells.
For example,
(i) despite the well-known presence of various auto-antibodies in ulcerative colitis patients (see Leiper et al., Gut 2011;60:1520e1526, cited herewith, at page 1520 col. bridging paragraph – 1st full paragraph), and
(ii) despite the depleting anti-CD20 antibody rituximab causing the percentage of peripheral blood lymphocytes that were CD19-postive B cells to drop from 3.93%-5.86% down to ≤ 0.08% in all patients who received rituximab at week 4, with similar drops in CD20 expression in colonic mucosal biopsies of patients who received rituximab (see page 1523, right col., 1st – 2nd full paragraphs), still
(iii) “Rituximab has no significant effect on inducing remission in moderately active UC unresponsive to oral steroids. There may be a modest therapeutic effect in the short term but no sustained effect.” (see final paragraph of Discussion on page 1525).
Likewise, as described by Mok et al. (Nephrology 19 (2014) 60–63, cited herewith), if anything the skilled artisan would have expected depletion of CD20 expressing cells to exacerbate psoriasis since (i) depletion of C20 expressing B-cells “…may have removed an unknown regulatory effect of B-cells on T-cells, which includes the polarization of T-cell responses,” and (ii) depletion of C20 expressing B-cells “…may also lead to impairment in the response to infection. Bacterial products can act as a trigger for psoriasis.” (see col. bridging 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, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001,(CAFC 1997), the court held: “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. Further, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
In conclusion, the instant specification provides insufficient teachings to guide the skilled artisan to treat the breadth of cancers encompassed by the instant claims. Undue trial and error experimentation would be required of the skilled artisan to begin discovering the breadth of diseases “characterized by the presence of CD20 expressing B cells” wherein the disease is psoriasis, psoriatic arthritis, dermatitis, systemic scleroderma and sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, chronic fatigue syndrome/myalgic encephalitis, chronic fatigue syndrome/myalgic encephalitis, uveitis, glomerulonephritis, eczema, asthma, atherosclerosis, leukocyte adhesion deficiency, multiple sclerosis, Raynaud's syndrome, Sjogren’s syndrome, juvenile onset diabetes, Reiter's disease, Behget's disease, immune complex nephritis, IgA nephropathy, IgM polyneuropathies, immune-mediated thrombocytopenia, acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, hemolytic anemia, myasthenia gravis, lupus nephritis, systemic lupus erythematosus, rheumatoid arthritis (RA), atopic dermatitis, pemphigus, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, contact dermatitis, linear IgA dermatosis, vitiligo, pyoderma gangrenosum, epidermolysis bullosa acquisita, pemphigus vulgaris, cicatricial pemphigoid, bullous pemphigoid, alopecia areata, alopecia universalis, alopecia totalis, dermatitis herpetiformis, erythema multiforme, chronic autoimmune urticaria, angioneurotic edema, or urticarial vasculitis, which can be successfully treated as claimed, and thus the breadth of the claimed methods of treatment is not enabled.
Claims 83 and 110-128 are allowed.
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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel E Kolker can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644