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. Claims 1-75 are pending.
Claims 6-34, 46-48, 54-57, 65-70, and 75 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims 6-34, 46-48, 54-57, 65-70, and 75 not been further treated on the merits.
Claims 1-5, 35-45, 49-53, 58-64, and 71-74 are currently under consideration.
3. 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.
4. Claims 1-5, 35-45, 49-53, 58-64, 73, and 74 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.
It is apparent that the hybridma that produces antibody VIB551 is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the hybridoma, which produces this antibody, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridoma described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
The instant specification discloses that the anti-CD19 antibody VIB551 comprises VH amino acid sequence of SEQ ID NO:1 and VL amino acid sequence of SEQ ID NO:2 (e.g. see [0026] of the instant specification as-filed). It is noted that the sequence of an entire immunoglobulin satisfies the biological deposit of said immunoglobulin. Note that satisfaction for the biological deposit of the specific 3G8 antibody requires the disclosure and recitation of its entire amino acid sequence and not based upon partial sequences.
Alternatively, amendment of the specification to recite the date of the deposit and the complete name and address of the depository is required. As an additional means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
5. Claims 71 and 72 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 71 and 72 are drawn to a method of treating neuromyelitis optica spectrum disorder (NMOSD) by administering an anti-CD19 antibody to a patient in need of treatment for NMOSD.
The specification discloses the VH and VL amino acid sequences of one anti-CD19 antibody VIB551 (e.g. see Table 1 in page 28 of the specification as-filed).
There is insufficient written description in the specification as-filed of a method of treating NMOSD by administering an anti-CD19 antibody as recited in the instant claims.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted. To show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Further, an adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Indeed, the courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
Artisans are well aware that knowledge of a given antigen (for instance human CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. (Protein Engineering Design & Selection 2009, 22;3:159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. (The Journal of Immunology, 2004, 173:7358-7367) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. (Nature Review Immunology, 2019, 19: 355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
It is noted that applicant has not claimed an anti-CD19 antibody, but rather a method of administering an anti-CD19 antibody. The artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has already been pointed out none of the instant claims recite any structure for the administered product that provides for the function treating NMOSD.
Thus, all present utilize only functional language to describe the product which is necessarily administered in the instant claims.
It is noted that the specification does disclose one anti-CD19 antibody VIB551. However, this single antibody species is not reasonably representative of the species of all possible anti-CD19 antibodies because of the structural diversity found in antibodies that bind the same antigen as discussed by for example Edwards et al., Llyod et al., and Goel et al. discussed above. Further, as has been discussed above, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide sufficient written description of the antibody in question.
Therefore, in view of the breadth of the claims and the generic nature of the instant specification, artisans would reasonably conclude that applicant was not in possession of the full breadth of the anti-CD19 antibodies at the time the instant application was filed. Logically, if applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
5. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
6. 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.
7. Claims 1, 35, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cree et al. (Lancet 2019; 394:1352-63, published online September 5, 2019) as evidenced by [0038] the instant specification as filed inebilizumab is VIB551.
Cree et al. teach treatment of neuromylitis optica spectrum disorder (NMOSD) by administering 300 mg anti-CD19 antibody inebilizumab intravenously on days 1 and 15 (e.g., see Methods in page 1352). Cree et al. further teach that one group of the patients is AQP4-IgG seropositive and also previously been treated with anti-CD20 antibody rituximab (e.g. see Table 1 in page 1356). As evidenced by [0038] of the instant specification as-filed, inebilizumab is anti-CD19 antibody VIB551. Cree et al. teach that compared with placebo, inebilizumab reduced the risk of an NMOSD attach (e.g. see page 1352).
As such, the reference teachings anticipate the instant invention.
8. Claims 1, 2, 35-37, 41, 42, 49, 50, 58, 59, 71, 72 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Levy et al. (ACTRIMS Forum 2021, Poster P145, February 2020, pages 1-10, reference on IDS) as evidenced by [0038] the instant specification as filed inebilizumab is VIB551.
Levy et al. teach the safety and efficacy of inebilizumab in those with previous rituximab exposure in NMOSD patients (e.g. see Title). Specifically Levy et al. teach that prior rituximab exposure did not impact efficacy of inebilizumab; seven of the seventeen patients experienced rituximab “failures” defined as having an NMOSD attach while on or within 6 month of the last dose of rituximab (e.g. see Result Summary). Levy et al. teach 92% of patients treated with inebilizumab is AQP4-Ig positive (e.g. see Table 1). Levy et al. teaches that inebilizumab treatment reduced attach frequency (e.g. see Figure 1).
As evidenced by [0038] of the instant specification as-filed, inebilizumab is anti-CD19 antibody VIB551.
Regarding the preamble of claims 36 and 37 method of reducing active MRI lesions), claims 41 and 42 (a method of reducing AQP4-IgG titers in AQP4-IgG+ patient), claims 49 and 50 (a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD), claims 58 and 59 (a method of reducing NMOSD-related attacks), note that here a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation. See MPEP 2111.02 II.
Here, while these preambles appear to drawn to different methods, the body of the claims recites the same or nearly the same process steps: administering the anti-CD19 antibody VIB551 to NMOSD patients previously treated with an anti-CD20 antibody. Given that the prior art teaches the method of treating the same patients with the same anti-CD19 antibody, the prior art teachings would anticipate the instant claims.
9. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 1-5, 35-45, 49-53, 58-64, and 71-74 are rejected under 35 U.S.C. 103 as being unpatentable over Cree et al. (Lancet 2019; 394:1352-63) or Levy et al. (ACTRIMS Forum 2021, Poster P145, February 2020, pages 1-10, reference on IDS), as evidenced by [0038] the instant specification as filed inebilizumab is VIB551 in view of Agius et al. [Multiple Sclerosis Journal 2019, 25(2):235-245] or Katz et al. (WO 2020/219743, reference on IDS).
The teachings of Cree et al. and Levy et al. have been discussed, above.
The reference teachings differ from the instant invention by not describing administering VIB551 intravenously at a dose of 300 mg every 6 months.
However, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature.
Although the prior art do not teach all the various permutations of interval ranges such as administering VIB551 intravenously at a dose of 300 mg every 6 month, it would be conventional and within the skill of the art to identify the optional intervals of treatment . Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
For example, Agius et al. teach safety and tolerability of inebilizumab in patients with relapsing forms of multiple sclerosis (MS) in a phase 1 randomized placebo-controlled escalating intravenous and subcutaneous dose study and show single subcutaneous dose on day 1 and a follow-up on week 24 (6 month) (e.g. see methods in page 235). Agius et al. teach that single dose SC administration of 300 mg inebilizumab has an acceptable safety profile and show reductions in new or newly enlarging lesions (e.g. see conclusion in page 235). Agius et al. teach B-cell depletion, duration of depletion remaining ⩾90% from baseline, and time to start of recovery were dose dependent, with most dose groups maintaining 90% depletion throughout the 24-week follow-up period (e.g. see left col. in page 242).
Agius et al. teach while B-cell depletion therapy with anti-CD20 antibodies has shown clinical benefit in patients with MS, preclinical data suggest that elimination of CD19+ plasmablasts and some plasma cells provide a greater clinical effect in B-cell-driven autoimmune disease (e.g. see 2nd paragraph in left col. in page 236).
Katz et al. teach a method of treating NMOSD by administering an anti-CD19 antibody VIB551, a humanized, affinity-optimized afucosylated IgG1 antibody (e.g. see Abstract). Katz et al. teach that administering the VIB551 to a NMOSD patient at a dosage of 300 mg every 6 month (e.g. see claim 1). Katz et al. also teach a method of reducing disability severity scale (e.g. see claim 2), a method of reducing number of MRI lesions (claim 4), a method of reducing NMOSD-related attack of the patient (claim 9). Katz et al. teach that the patient is AQP4-IgG seropositive (claim 26). Katz et al. further teach clinical trial includes patients had been previously treated with anti-CD20 antibody rituximab (e.g. see Table 9 in page 55).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to administered inebilizumab at 300 mg either intravenously or subcutaneously to NMOSD patients. This is because administering inebilizumab at 300 mg to treat NMOSD patients previously treated with anti-CD20 antibody were done by Cree and Levy. Both Cree and Levy teach that inebilizumab reduced the NMOSD attack. Agius et al. teach inebilizumab administered at 300 mg maintaining 90% B cell depletion throughout the 24 weeks (6 month) follow up period. Katz et al. teach administering VIB551 300 mg every 6 months. Given that it was known that inebilizumab maintain 90% B cell depletion throughout 24 weeks and that it can be administered 300 mg every 6 months, an ordinary skill in the art would have been able to combine the reference teachings to administer the antibody to NMOSD patients previously treated with an ant-CD20 antibody with unstratified results, e.g. having NMOSD attack while being treated with the anti-CD20 antibody, with a reasonable expectation of success.
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641