DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 08/22/2023, is acknowledged.
3. Claims 1-6 are pending and under examination.
4. Claim 5 is objected to because “inflammatory bowel disease” encompasses only two species “Crohn’s disease” and “ulcerative colitis” which already recited in the claim. The claim recites the subgenus of IBD as well as its species CD and UC as part of the genus of “autoimmune or inflammatory disease”. It is suggested that the claim be amended to delete either “inflammatory bowel disease” or “Crohn’s disease” and “ulcerative colitis” to solve the issue.
5. Applicant’s IDS, filed 08/22/2023, is acknowledged.
6. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
7. Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing 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 specification does not reasonably provide enablement for broad genus methods of treating an autoimmune or inflammatory disease in a patient in need thereof with the claimed anti-CD47 antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification does not provide empirical data to show the efficacy of the claimed anti-CD47 antibody B06, B5712 and B5715 on autoimmune or inflammatory disease including a Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave's disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis and ankylosing spondylitis. No working empirical data demonstrating that the the anti-CD47 antibody would treat autoimmune or inflammatory disease.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification disclosure does not enable one skilled in the art to practice the invention without an undue amount of experimentation. The specification lacks empirical data on the in vivo efficacy of anti-CD47 antibody B5712 and B5715. It is noted that the specification does not provide exemplification or animal model to treat the claimed genus of autoimmune or inflammatory diseases in a patient with B5712 and B5715. Although Applicant's specification describes that the new CD47 antibodies (B5711 to B5716) resulted in essentially no RBC agglutination at the tested concentrations up to 150 pg/mL ([0069], [0180] FIG. 6). The tested antibodies exhibited potent binding and inhibitory activities and are useful for therapeutic and diagnostics uses [0069]. The specification at [0005] discloses that anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but also fosters the activation of cancer-specific lymphocytes. Anti-CD47 antibodies are being evaluated for the treatment of various cancers, e.g., relapsed/refractory B-cell non-Hodgkin's lymphoma, solid tumors, colorectal cancer, ovarian cancer, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The examples provided in the specification demonstrate that the claimed anti-CD47 antibody promotes phagocytosis of tumor cells by human ([0006] example 8, Fig. 8). There is no correlation on this record between the phagocytosis of tumor cells by human experiments and a practical method of in vivo use in currently available form for patients suffering from autoimmune or inflammatory diseases. It is not enough to rely on cancer model studies where a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to methods of in vivo use in patient having autoimmune or inflammatory diseases. Ex parte Maas, 9 USPQ2d 1746. There must be a rigorous correlation of pharmacological activity between the disclosed in cancer model use and in vivo methods of treating autoimmune or inflammatory diseases to establish practical methods of use.
Lu et al (J. Biol. Chem. (2025) 301(8) 110420) generated Hu1C8, a humanized anti-CD47 monoclonal antibody that demonstrated increased selectivity for binding to CD47 on cancer cells and lacked hemagglutination activity. Epitope mapping and the crystal structure of the Hu1C8 Fab-CD47 extracellular domain (ECD) complex revealed that Hu1C8 binds to a distinct epitope of CD47 in a Ca2+-dependent manner. The unique recognition and binding mode allowed Hu1C8 to bind CD47 on RBCs with reduced hemagglutination activity while still maintaining effective antitumor activity. These findings demonstrate a feasible strategy for developing CD47 antibodies with high antitumor activity but low RBC hemagglutination activity. Their study elucidates how epitope-specific antibody influences antibody-induced cell cross-linking, offering innovative strategies for antibody design to either leverage or avoid cell cross-linking effects. (abstract). Lu et al teach that results reaffirm that epitope localization critically governs antibody activity and provides a structural basis for the rational design of therapeutic mAbs with tailored functional properties. For anti-CD47 antibodies, selecting the antigen-binding epitope is particularly important to avoid hemagglutination caused by cell crosslinking (see page 9, left col., 2nd ¶).
Han et al (J. Exp. Med. 2012, 209 (7):1325-1334) demonstrate that CD47-/- mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system (see Abstract). Han et al demonstrated that modulating CD47 function during initiation and progression has opposing effects in the peripheral immune system and the CNS during autoimmune neuroinflammation (page 1326, left col, 1st ¶). Han et al hypothesized that blocking CD47 with mAb (mAb CD47) would ameliorate neuroinflammation. However, they observed that WT EAE mice treated with mAb CD47 by daily i.p. injections at the point of maximal paralysis worsened EAE severity compared with IgG-treated control mice (Fig. 4 A). This was accompanied by enhanced immune cell proliferation and inflammatory cytokine production in the spleens and lymph nodes (Fig. 4, B–F). In support of this finding, they observed that EAE mice treated with mAb against CD47 at the time of immunization developed less severe EAE (Fig. S5) (see page 138, right col., 1st ¶). Accordingly, CD47 plays dual and contradictory role during neuroinflammation, which are likely caused by differential expression of CD47 in different cell types, location, and disease phase.
Oldenborg et al (Blood. 2002;99:3500-3504) show here that virtually all CD47-deficient nonobese diabetic (NOD) mice spontaneously develop severe lethal autoimmune hemolytic anemia (AIHA) at 180 to 280 days of age, whereas none of the control CD47 NOD mice develop lethal AIHA at least during the first year of life. This phenotype is at least partially due to a markedly increased rate of elimination of opsonized CD47/ compared to CD47 RBCs. Similarly, CD47/C57BL/6 mice were much more sensitive than their wild-type counterparts to experimental passive AIHA induced by anti-RBC monoclonal antibodies. Oldenborg et al show that CD47 deficiency results in lethal autoimmune haemolytic anaemia (AIHA) in non-obese diabetic mice.
In re Fisher, 166 USPQ 18 indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. One cannot extrapolate the teachings of the specification to the scope of the claims because the method claims are drawn to treating autoimmune or inflammatory disease including a Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave's disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis and ankylosing spondylitis using B5712 and B5715. No working empirical data demonstrating that anti-CD47 antibody B5712 and B5715 would be use in the claimed methods. The specification lacks empirical data on the in vivo efficacy of the claimed anti-CD47 antibodies on subjects including human. The experiments in the specification never successfully used the claimed anti-CD47 antibody in treating autoimmune or inflammatory disease including a Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave's disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis and ankylosing spondylitis in a subject. Based on the absence of a specific and detailed description in Applicant's specification of how to effectively use the methods as claimed, and absence of working examples providing evidence which is reasonably predictive that the claimed methods are effective for treating Crohn’s disease in a subject, and the lack of predictability in the art at the time the invention was made, an undue amount of experimentation would be required to practice the claimed methods with a reasonable expectation of success. There is no evidence of record that demonstrates that the anti-CD47 antibodies can be used to treat autoimmune or inflammatory diseases. The specification fails to provide working examples providing evidence which is reasonably predictive that the claimed methods are effective for the treatment of autoimmune or inflammatory diseases. The lack of any working examples is exacerbated because the invention is in a highly unpredictable art- autoimmune or inflammatory diseases- and while the level of skill of in the art may be high, the state of the prior art is that it is in fact unknown and untested.
The specification disclosure does not enable one skilled in the art to practice the invention without any undue amount of experimentation. The specification lacks empirical data on using pathogenic principles to design and test specific the claimed anti-CD47 antibodies in animal models with the prospect of ultimate relevance in human disease. However, on the basis of the disclosed apparent in vivo cancer treatment observation alone, applicant concludes that the scope of the invention can have biological activity to treat autoimmune or inflammatory diseases and be provided as pharmaceutical compositions to patients.
The MPEP states that the issue of "correlation" is dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. See MPEP 2164.02.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
8. No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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February 9, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644