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 01/26/2026, is acknowledged.
3. Claims 1-5, 14-26, 29-35 are pending.
4. Applicant’s election the following species:
i) dosing regimen of 800 µg on day 1 (first dose), 4.5 mg on day 3 (second dose), 9 mg on day 5 (third dose), and18 mg on days 8, 15, and 22 (target dose), whereby the third dose is required.
(ii) wherein the method further comprises subsequent cycles at a dose of 18 mg on days 1, 8, 15, and 22.
(iii) multiple myeloma as the BCMA-positive neoplasm.
(iv) BCMA antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 171-176, VH and VL of SEQ ID NOs: 177 and 178, target-binding domain and proteins of SEQ ID NO: 179 and 661 and ) CD3 antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 636-638, 633-635, VH and VL of SEQ ID NOs: 639 and 641, target-binding domain and proteins of SEQ ID NO: 642 and 661; filed on 01/26/2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a).
5. Claims 19, 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-5, 14-18, 20-26, 29-31, 34-35 are under examination as they read on the following species i) dosing regimen of 800 µg on day 1 (first dose), 4.5 mg on day 3 (second dose), 9 mg on day 5 (third dose), and18 mg on days 8, 15, and 22 (target dose), whereby the third dose is required.
(ii) wherein the method further comprises subsequent cycles at a dose of 18 mg on days 1, 8, 15, and 22.
(iii) multiple myeloma as the BCMA-positive neoplasm.
(iv) BCMA antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 171-176, VH and VL of SEQ ID NOs: 177 and 178, target-binding domain and proteins of SEQ ID NO: 179 and 661 and ) CD3 antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 636-638, 633-635, VH and VL of SEQ ID NOs: 639 and 641, target-binding domain and proteins of SEQ ID NO: 642 and 661.
7. Applicant’s IDS, filed 07/28/2023, 01/09/2025, is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
9. Claims 1-5, 14-18, 20-26, 29-31, 34-35 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The recitation "preferably ..." in claims 3, 5, 17, 18, 21, 29, is indefinite because the narrow range within the broad range using the term “preferably” renders the claim indefinite.
(ii) The recitation “about X mg/day” in claims 1, 4, 5, 16, 17 is indefinite for reciting. It is unclear how many “mg” constitutes “about”. One of skill in the art would not know if applicant meant 0.1 mg, 0.2 mg or 0.4, or even more constitutes “about”.
(iii) the recitation “optionally” in claims 2, 3, 14, 17-18 are indefinite. The alternative options list of potential alternatives can vary and ambiguity arises and confusing. Claims 2 and 17 indicate that the administration of third dose is optional, claims 3 and 18 indicates that the administration of third dose on day 5, or 6, 8, 15 and 22 is optional this is confusing.
10. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
11. Claims 1-5, 14-18, 20-26, 29-31, 34-35 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass a broad genus of protein comprising a first domain which binds to CMA, a second domain which binds to CD3 and a third domain which extends the half-life of the protein in the treatment and amelioration of BCMA-positive neoplasm in the subject.
Claim 24 encompasses a broad genus of BCMAXCD3 bispecific antibodies that compete for binding to BCMA with or binds to the same epitope of BCMA as a reference antibody recited in the claim.
Claim 25 encompasses a broad genus of BCMAXCD3 bispecific antibodies that compete for binding to CD3 with or binds to the same epitope of CD3 as a reference antibody recited in the claim.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of treatment and amelioration of BCMA-positive neoplasm. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification at [0272] discloses that a protein comprising a first domain which binds to BCMA, a second domain which binds to CD3 and a third domain which extends the half-life of the protein, for use in the treatment or amelioration of a BCMA positive neoplasm.
[0295] The protein of the invention (and the pharmaceutical composition comprising such protein) is/are useful in the treatment and/or amelioration of the BCMA positive neoplasm as described herein in a subject in need thereof. The term “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. The prophylactic measure usually refers to a situation where the relapse (recidivism/recurrence) of a neoplasm is to be prevented. Treatment includes the administration of the protein (or the pharmaceutical composition comprising such protein) to the patient's body, to an isolated tissue, or to a cell from a patient or a subject in need who has a BCMA positive neoplasm as described herein, a symptom of such neoplasm, or a predisposition toward such neoplasm, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the BCMA positive neoplasm, one or more symptoms of the BCMA positive neoplasm, or the predisposition toward the disease or its recurrence.
[0379] The protein to be administered according to the present invention comprises a first domain which binds to BCMA and a second domain which binds to CD3 and is hence “at least bivalent” and “at least bispecific”. In certain embodiments, the protein used in the methods of the invention is multivalent. The valency of the binding protein denotes the number of individual antigen-binding domains within the protein. For example, the terms “monovalent.” “bivalent,” and “tetravalent” with reference to the protein in the context of the invention refer to proteins with one, two, and four antigen-binding domains, respectively. Thus, a multivalent protein comprises two or more antigen-binding domains. A protein according to the invention can have more antigen-binding domains (e.g. a higher valency) than specificities. For instance, in a case where it has two binding domains for the first target (BCMA) and one binding domain for the second target (CD3)—or vice versa—the construct would be (at least) trivalent and bispecific. The protein may hence be bivalent, trivalent, tetravalent or multivalent/polyvalent.
[0382] The interaction between the binding domain and the target antigen implies that a binding domain exhibits appreciable or significant affinity for the target antigen (here: BCMA and CD3, respectively). In general, it does furthermore not exhibit significant affinity for proteins or antigens other than the target antigen (here: BCMA/CD3)—notwithstanding the above discussed cross-reactivity with homologous targets e.g. from other species. “Significant affinity” includes binding with an affinity (dissociation constant, KD) of ≤10−6 M.
[0631] Background: AMG 701, an HLE BITER molecule which binds BCMA on Multiple Myeloma (MM) cells and CD3 on T cells, has activity in MM preclinical models. Objectives of this first-in-human study include evaluating safety and estimating the maximum tolerated dose (MTD) of AMG 701 in patients with relapsed/refractory (R/R) Multiple Myeloma (NCT03287908).
It is noted that human BCMA is 132 amino acid in length and CD3 is 201 amino acid long. It is well known in the art that the epitope binding site of an antibody is usually defined by no more than six to eight amino acids. Neither the instant specification nor the art of record shows that the majority of antibodies that bind to any one of the multitude of epitopes present in a protein having the sequence of BCMA and CD3 are capable of treat or ameliorate a BCMA-positive neoplasm such as MM in a subject, as is required for the operability of the claimed product. The required genus is not adequately described because neither the specification nor the art of record describes a representative number of species of antibody within the required genus.
Artisans are well aware that knowledge of a given antigen (for instance Galectin-9) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al (J Mol Biol. 2003 Nov 14;334(1): 103-18) 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 FICDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al (Protein Eng Des Sel. 2009 Mar;22(3):159-68) 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 (J Immunol. 2004 Dec 15; 173(12):7358-67) 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 (Nat Rev Immunol. 2019 Jun; 19(6):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 x 1014).
Importantly, the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of the BCMA and CD3 in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, one or more functions recited in the claims and binding affinity, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed BCMAXCD3 bispecific antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the BCMAXCD3 bispecific antibodies are required to practice the invention. The specification fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of BCMA and CD3 as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of BCMAXCD3 bispecific antibodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed BCMAXCD3 bispecific antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Claims 24-25 require the BCMAXCD3 bispecific antibodies “competes for binding to BCMA/CD3 with or binds to the same epitope of BCMA/CD3 as” an antibody recited in claims 24-25. While the amino acid sequences of BCMA/CD3 was known, immunizing an animal with BCMA/CD3 will generate antibodies directed to a number of different epitopes within the amino acid residues at positions bound by the claimed antibody and not necessarily to the same epitope which is bound by the claimed antibody recited in claims 24-25. The knowledge of the amino acid sequence of BCMA/CD3, by itself, did not put Applicants in possession of antibodies that binds the same epitope as the epitope bound by the claimed BCMAXCD3 bispecific antibodies.
This case is similar to Centocor Ortho Biotech, Inc. v. Abbott Laboratories, 636 F.3d 1341 (Fed. Cir. 2011). In Centocor, patentee claimed an antibody or antibody fragment that competitively inhibits binding of A2 (a mouse antibody) and that binds an epitope of TNF-α with a specified affinity. 636 F.3d at 1346. Both TNF-α protein and antibodies to that protein were known in the literature. Id. at 1352. Patentee argued that the patent at issue satisfied the written description for the claimed antibodies because it "not only describes the antibodies by their binding affinity for TNF-α, but further describes the antibodies by specifying that they competitively inhibit binding of the A2 mouse antibody to TNF-α." Id. At 1349. The Federal Circuit rejected this argument, finding that "[a]t bottom, the asserted claims constitute a wish list of properties that a fully-human, therapeutic TNF-α antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse A2 antibody." Id. At 1351. The court explained that "[t]he specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations."
In finding that the specification at issue did not provide written description support for the claimed antibodies, the Centocor court recognized that the written description does not require examples or an actual reduction to practice, but clarified that "it does demand ... that one of skill in the art can 'visualize or recognize' the claimed antibodies based on the specification's disclosure." Id. at 1353. "In other words the specification must demonstrate constructive possession." Id; see also, AbbVie Deutschland GmbH & Co., KG., v. Janssen Biotech, Inc., 759 F.3d 1285, 1301 (Fed. Cir. 2014) (reiterating requirement for structure-function correlation in functionally defined claims and finding that the patents at issue do not meet the written description requirement because they "do not describe any common structural features of the claimed antibodies.").
Here, as in Centocor, Applicant seeks to ground written description support for a claimed antibody in its competitive inhibition of another antibody (here, the monoclonal antibodies AMG 701, in Centocor, mouse A2 antibody) and in the description of a known antigen (here BCMAXCD3, in Centocor, TNF-α). While the state of the art has progressed since the Federal Circuit's decision in Centocor, the basic problem remains that the description at issue must allow one of skill in the art to "visualize or recognize" the claimed antibodies. Here, the evidence of record does not support that the skilled artisan would have visualized or recognized the claimed antibodies based on the description provided. As in Centocor, the Specification provides only a plan for identifying the claimed antibodies.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of anti-Galectin competing antibodies falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
12. 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
13. Claims 1-5, 14-16, 21-26, 29-31, 34-35 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by The 20230398147, of record.
The `147 publication teaches AMG 701 is an HLE BiTE® molecule that binds both B-cell maturation antigen (BCMA) and CD3 and comprises a single chain IgG Fc domain (extends the half-life of the BiTE). The amino acid sequence of AMG 701 is set forth in SEQ ID NO: 50. This study is a phase 1 open-label, dose-exploration study to evaluate the safety, tolerability, and efficacy of AMG 701 in patients who have relapsed/refractory multiple myeloma [0272]. [0296] Patients are dosed in each of four cohorts as follows: [0297] Cohort 1: priming dose of 8.4 mg administered by continuous IV infusion over 7 days (e.g. 1.2 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0298] Cohort 2A: priming dose of 16.1 mg administered by continuous IV infusion over 7 days (e.g. 2.3 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0299] Cohort 2B: priming dose of 4.6 mg administered by continuous IV infusion over 2 days (e.g. 2.3 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 0.8 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] Cohort 3: priming dose of 9.2 mg administered by continuous IV infusion over 2 days (e.g. 4.6 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 1.6 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0322], [0322].
The `147 publication teaches that the first dose (e.g. priming dose) of AMG 701 is administered as a continuous IV infusion over the course of 2 or 7 days during the first week of cycle 1 followed by weekly short-term IV infusions (e.g. 60-minute IV infusions) of the target dose of AMG 701 beginning on day 8 of the cycle. AMG 701 is administered in 28-day cycles and the date of the first dose of AMG 701 is defined as day 1 in the cycle. Without being bound by theory, these continuous IV priming dosing regimens are believed, based on PK simulations, to achieve the serum free AMG 701 projected efficacious exposures within 2 to 4 days, but more importantly they are also predicted to avoid any rapid increase in free AMG 701 serum exposures as seen with short-term 60-minute IV infusions with a sharp increase in free AMG 701 serum concentrations, e.g. a peak serum concentration (Cmax) within 1 hour of infusion start. A slow ramp up in free AMG 701 concentrations and delaying the time to Cmax is believed to reduce the risk of CRS. These cIV priming dosing regimens are believed to enable optimal T cell engagement of target cells during week 1, without rapid increases in serum concentrations of free AMG 701, which have been associated with induction of Grade 2 and higher CRS following initial cycle 1 doses of AMG 701 administered by 60-min IV infusions [0294].
AMG 701 comprise all the claimed SEQ ID NOs, molecular weight and half-life.
The reference teachings anticipate the claimed invention.
14. 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.
15. Claims 1-5, 14-18, 20-26, 29-31, 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Harrison et al (Blood (Nov. 5, 2020) 136 (Supplement 1, of record) : 28) and/or US 20210139584 (of record) and/or US 20230398147 (of record), in view of in view of Goldstein et al (Blood Adv (Sept. 4,2020) 4 (17): 4180–4194, of record).
Harrison et al teaches that patients with Relapsed/Refractory Multiple Myeloma (MM RR) or intolerant to ≥3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. The first 3 cohorts (dose 5-45 μg) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, ≤10-5 per IMWG) or flow cytometry (≤3×10-5).
The response rate was 36% (16/45) at doses of 3-12 mg; at ≤1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values.
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Claims 4 and 5 included because these claims depend from claim 2, which recites that the third dose is optional.
Claim 15 is included because the AMG 701 IV infusions weekly in 4-week cycles, (i.e., days 1, 8, 15, 22; 1, 15, 22; . . .).
Claim 16 is included because the reference teaches 4-week cycles (i.e., 28 days).
Claims 24-26 29, are included because AMG 701 comprises the claimed BCMA antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 171-176, VH and VL of SEQ ID NOs: 177 and 178, target-binding domain and proteins of SEQ ID NO: 179 and 661 and ) CD3 antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 636-638, 633-635, VH and VL of SEQ ID NOs: 639 and 641, target-binding domain and proteins of SEQ ID NO: 642 and 661.
Claim 34 is included because AMG 701 has 105.78 Kda.
Claim 35 is included because AMG 701 has 112 hours (4.7 days) half-life.
The `584 publication teaches and claims methods of treating or ameliorating a B-cell maturation antigen (BCMA) positive neoplasm comprising administering an antibody construct comprising a first domain which binds to BCMA, a second domain which binds to CD3 and a third domain which extends the half-life of the antibody construct, wherein the antibody construct is administered at a minimum dose of 800 μg/day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct, wherein the antibody construct is administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more cycles, wherein one cycle has a) about 25 to about 30 days, b) about 26 or 27 to about 29 days, or c) about 28 days, wherein the antibody construct is administered at a dose of about 800 μg/day to 12 mg per day, such as 1000 μg, 1200 μg, 1500 μg, 1600 μg, 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg or 12 mg per day, wherein the antibody construct is administered in one or two dose steps during the first cycle, wherein a first dose is between 800 μg/day and 1200 μg/day, an optional second dose is between 2500 μg/day and 5000 μg/day, preferably about 3000 μg/day or about 4500 μg/day, and a last dose (target dose) is between 6500 μg/day and 12 mg/day, such as 6500 μg/day, 7000 μg/day, 7500 μg/day, 8000 μg/day, 8500 μg/day, 9000 μg/day, 9500 μg/day, 10 mg/day, 11 mg/day or 12 mg/day. The `584 publication teaches that after a grade 3 dose-limiting toxicity (DLT) of cytokine release syndrome (CRS) at 1600 μg, for all target doses ≥1200 μg, an initial run-in dose of 800 μg was added, followed by step up to the target dose. 47 patients received AMG 701 at doses ranging from 5 to 6500 μg, with an 800 μg run-in dose used for step-up to target doses of ≥1200 μg; patients are yet to be enrolled at additional planned doses of 9000 and 12000 μg, see also FIG. 1 [0517].
The 20230398147 publication teaches AMG 701 is an HLE BiTE® molecule that binds both B-cell maturation antigen (BCMA) and CD3 and comprises a single chain IgG Fc domain (extends the half-life of the BiTE). The amino acid sequence of AMG 701 is set forth in SEQ ID NO: 50. This study is a phase 1 open-label, dose-exploration study to evaluate the safety, tolerability, and efficacy of AMG 701 in patients who have relapsed/refractory multiple myeloma [0272]. [0296] Patients are dosed in each of four cohorts as follows: [0297] Cohort 1: priming dose of 8.4 mg administered by continuous IV infusion over 7 days (e.g. 1.2 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0298] Cohort 2A: priming dose of 16.1 mg administered by continuous IV infusion over 7 days (e.g. 2.3 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0299] Cohort 2B: priming dose of 4.6 mg administered by continuous IV infusion over 2 days (e.g. 2.3 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 0.8 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] Cohort 3: priming dose of 9.2 mg administered by continuous IV infusion over 2 days (e.g. 4.6 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 1.6 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0322], [0322].
The `147 publication teaches that the first dose (e.g. priming dose) of AMG 701 is administered as a continuous IV infusion over the course of 2 or 7 days during the first week of cycle 1 followed by weekly short-term IV infusions (e.g. 60-minute IV infusions) of the target dose of AMG 701 beginning on day 8 of the cycle. AMG 701 is administered in 28-day cycles and the date of the first dose of AMG 701 is defined as day 1 in the cycle. Without being bound by theory, these continuous IV priming dosing regimens are believed, based on PK simulations, to achieve the serum free AMG 701 projected efficacious exposures within 2 to 4 days, but more importantly they are also predicted to avoid any rapid increase in free AMG 701 serum exposures as seen with short-term 60-minute IV infusions with a sharp increase in free AMG 701 serum concentrations, e.g. a peak serum concentration (Cmax) within 1 hour of infusion start. A slow ramp up in free AMG 701 concentrations and delaying the time to Cmax is believed to reduce the risk of CRS. These cIV priming dosing regimens are believed to enable optimal T cell engagement of target cells during week 1, without rapid increases in serum concentrations of free AMG 701, which have been associated with induction of Grade 2 and higher CRS following initial cycle 1 doses of AMG 701 administered by 60-min IV infusions [0294].
AMG 701 comprise all the claimed SEQ ID NOs, molecular weight and half-life.
The reference teachings differ from the claimed invention only in the recitation that the target dose from 12.5 mg/day to about 24mg/day in claim 1, or 18 mg/day in claims 4, 17, 19, 20.
Goldstein et al teach in a subcutaneous mouse xenograft model, at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). Dose-dependent pharmacokinetic and pharmacodynamic behavior was observed, with depletion of PC-specific genes reaching 93% in blood and 85% in BM.
Given that at all doses tested, AMG 701 completely inhibited tumor formation, further the Harrison et al, US 20210139584 and US 20230398147 applicant indicates a success using 12 mg/day target dose in the treatment of MM, those of skilled in the art would use 18 mg/day as the target dose with reasonable expectation of success since lower doses were efficient to inhibited MM, then a higher target dose of up to 24 mg/day would also be effective in treating. If one skilled in the art, based upon knowledge of compounds having similar physiological or biological activity, would be able to discern an appropriate dosage or method of use.
The claimed dose escalation of 800µg/day on d1, 2nd dose of 405 mg/day on d3, 3rd dose of 9 mg on d5 and the target dose of 18 mg/day on d8 , 18, 22 is considered obvious variation of the prior art does regimen to reduce the risk of CRS and effectively treat MM. A person having ordinary skill in the art would have found it obvious to determine the optimum dose regimen for AMG 701 BiTE that enhances anti-tumor effect and reduce the risk of CRS of result-effective variables known in the art. Recognition that a property (promoting anti-tumor effect and reducing the riski of CRS) is affected by the variable (dose regimen of AMG 701) is sufficient to find the variable result-effective. The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720. The experimentation needed to arrive at the subject matter claimed was "nothing more than routine" application of a well-known problem-solving strategy, we must conclude it is not invention. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007).
It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal concentrations of components because concentration is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. 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.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellants' claims and arguments fail under these tests.
Contrary to Appellants' arguments, the claims do not recite that their pharmaceutical composition is commercially viable or has a specific shelf- life or has a specific stability. Nor does the Specification discuss these qualities or suggest that they were even considered by Appellants in relation to the single unit dosage of the claims. Similarly, the Appellants-argued points on mitigation of waste, and storage, waiting, and drug vial multiplication do not address claim limitations and are not discussed in the Specification. See Br. 7-8. In fact, the Specification does not indicate a single advantage of the single unit dosage of the claims. Moreover, Appellants present no compelling evidence of secondary indicia of non- obviousness to rebut the Examiner's prima facie case of obviousness. Thus, there is no evidence that the optimization of the single unit dosage was anything but routine and it is well settled that arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135, 139-40 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699,705 (Fed. Cir. 1984).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
16. 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17. Claims 1-5, 14-18, 20-26, 29-31, 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 17-18, 21 and 24-39 of copending Application No. 16869793 (reference application) optionally in view of Goldstein et al (Blood Adv (Sept. 4,2020) 4 (17): 4180–4194). Although the claims at issue are not identical, they are not patentably distinct from each other because the `793 application is directed to method of treating multiple myeloma with anti-BCMAXCD3 BiTE antibody (AMG 701) comprising the claimed SEQ ID NOs comprising a dose administration in a single day and other administrations of the cycle are administered on different days, wherein the cycle is up to 25 or more cycles, wherein one cycle is 25 to 30 days, wherein the antibody is administered at a dose of 800 µg/day to 12 mg per day, wherein the antibody is administered in one or two dose steps during the first cycle, wherein the cycle comprising at least three administrations comprises a first dose between 800-1200 µg/day, a second dose between 2500-5000 µg/day, and a third or last dose between 6500 µg/day and 12 mg/day, wherein the fist cycle comprises four, five, or six individual administrations of the antibody construct, wherein the antibody is administered at constant doses during the second cycle, wherein the antibody construct is administered parenterally including intravenous, wherein the dose include 800 µg/day, 4500 µg/day, 900 µg/day and 12mg/day, wherein the second dose is between 3000 µg/day and 4500 µg/day, wherein the last dose is 12 mg/day.
The reference teachings differ from the claimed invention only in the recitation that the target dose from 12.5 mg/day to about 24mg/day in claim 1, or 18 mg/day in claims 4, 17, 19, 20.
Goldstein et al teach in a subcutaneous mouse xenograft model, at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). Dose-dependent pharmacokinetic and pharmacodynamic behavior was observed, with depletion of PC-specific genes reaching 93% in blood and 85% in BM.
Given that at all doses tested, AMG 701 completely inhibited tumor formation, further the `793 applicant indicates a success using 12 mg/day target dose in the treatment of MM, those of skilled in the art would use 18 mg/day as the target dose with reasonable expectation of success since lower doses were efficient to inhibited MM, then a higher target dose of up to 24 mg/day would also be effective in treating.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18. No claim is allowed.
19. 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 24, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644