DETAILED ACTION
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 .
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 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/01/2024 has been entered.
Claims 1-24 are cancelled and claim 31 is new. Claims 25-31 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 04/12/2020, is a 371 filing of PCT/US2018/060737, filed 11/13/2018, and claims domestic benefit to US provisional application 62/584,171, filed 11/10/2017.
Withdrawn Objections and Rejections
In the office action of 05/01/2024:
Claims 25 and 27 were rejected under 35 USC 103 over Sanofi in view of Sollini, Jurcic , Hagemann, and EP’746 as evidenced by Maguire. The rejections are withdrawn in favor of the modified rejections of the instant office action.
Claims 26 and 28 were rejected under 35 USC 103 over Sanofi in view of Sollini, Jurcic, Hagemann, EP’746, and Maguire. The rejections are withdrawn in favor of the modified rejections of the instant office action.
Claim 29 was rejected under 35 USC 103 over Sanofi in view of Sollini, Jurcic, Hagemann, EP’746, Maguire, and Suey. The rejections are withdrawn in favor of the modified rejections of the instant office action.
Claim 30 was rejected under 35 USC 103 over Sanofi in view of Sollini, Jurcic, Hagemann, EP’746, and Suey. The rejections are withdrawn in favor of the modified rejections of the instant office action.
Claim Objections
Claim 25, fourth line from the bottom has an underline between the “of” and “HuM195”, stating “of_HuM195”. The space was previously added in the claim and the underline should be removed.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 25, 27-28, and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Jurcic, J.G., et al (2011) Abstract 615. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in acute myeloid leukemia (AML) Blood 118(21); 768 (herein “Jurcic615”) in view of Dos Santos, C., et al (2014) Abstract 616. Anti-Leukemic activity of daratumumab in acute myeloid leukemia cells and patient-derived xenografts Blood 124(21); 2312, US 2011/0262454 A1 (Sanofi-Aventis) 27 OCT 2011, EP 0337746 (Beatty, J.D. and B. G. Beatty) 18 OCT 1989, Hagemann, U.B., et al (2016) In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the treatment of Acute Myeloid Leukemia Mol Cancer Ther 15(10); 2422-2431, and Suey, C.M., et al. (1990) Radioimmunotherapy with Monoclonal antibodies Journal of Nuclear Medicine Technology 18(3) 176-183 as evidenced by Maguire, W.F., et al (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for α-particle radioimmunotherapy of cancer The Journal of Nuclear Medicine 55(9); 1492-1498.
Jurcic615 teaches that lintuzumab (anti-CD33; HuM195) is a humanized anti-CD33 antibody that has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 was conjugated to lintuzumab and demonstrated substantial clinical activity. Jurcic615 teaches that the use of 213Bi is limited by its 46-min half-life; however, the isotope generator 225Ac has a half-life of 10 days, yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN (page 1, paragraph 1; Title). The DOTA-SCN in the conjugate taught by Jurcic615 is a chelator that chelates the 225Ac as evidenced by Maguire (page 1492, right column, paragraph 2; page 1493, left column, paragraph 3).
Jurcic615 reports the results of a phase I dose escalation trial of 225Ac-lintuzumab in relapsed or refractory AML patients. Patients in the study received a single infusion of 225Ac-lintuzumab at doses of 0.5, 1, 2, 3, or 4 μCi/kg (page 2, paragraph 1).
Jurcic615 reports that peripheral blood blasts were eliminated in 64% of patients at dosages ≥ 1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤ 5% (page 2, paragraph 1).
Jurcic615, however, does not disclose that the 225Ac-HuM195 is administered in a composition further comprising an unlabeled fraction or that the composition is administered in combination with 225Ac labelled/unlabeled daratumumab as claimed.
Dos Santos teaches that daratumumab is a human antibody that binds CD38 on the cell surface and induces cell killing by multiple mechanisms including CDC, ADCC, ADCP, and apoptosis (page 1, paragraph 1). Dos Santos evaluated the anti-leukemic activity of daratumumab in therapeutic xenograft models using 3 different AML patients. NSG mice were transplanted with T-cell depleted AML cells and treated with daratumumab once a week for five weeks. AML burden, % huCD45+ CD33+, in bone marrow, spleen, and peripheral blood was evaluated within 5 days of the last treatment. Daratumumab was shown to significantly reduce leukemia burden in the spleen and peripheral blood, but not in the bone marrow. Daratumumab was also seen to reduce CD38 surface expression in AML, including bone marrow blasts, demonstrating that daratumumab efficiently targeted CD38 in bone marrow blasts (page 2, paragraph 2).
Sanofi teaches therapeutic methods of killing CD38+ cells by administering to a patient in need thereof an antibody which binds CD38 and is able to kill the cell by apoptosis, ADCC, and/or CDC (page 25, [0342]). Sanofi further teaches that the CD38 antibodies are used in therapeutic compositions comprising a second therapeutic agent and that the second therapeutic agent can be chosen from a group including antibodies targeting clusters of differentiation (CD) antigens including CD33 (pages 2-3, [0021]). Sanofi further teaches that the disclosed compositions can be used for the treatment of hyperproliferative disorders (page 25, [0343]) including acute myeloid leukemia (page 25, [0344]).
Sanofi further teaches pharmaceutical compositions comprising an effective amount of an anti-CD38 antibody and a pharmaceutically acceptable carrier (page 24, [0331]-[0333]). Sanofi teaches that the compositions may also include an additional therapeutic agent, as necessary for the particular disorder being treated, including CD33 targeting agents (page 24, [0335]).
EP’746 teaches compositions for therapy and teaches methods comprising administering a labeled and unlabeled antibody to a mammal (abstract). EP’746 teaches that the disclosed invention is related to methods for enhancing biodistribution in a mammalian subject and specifically related to the use of monoclonal antibodies for localization, detection, and treatment of lesions, including tumors. EP’746 further teaches that the diagnostic and therapeutic use of radioactively labeled antibodies specific to substances produced by or associated with tumors is recognized in the prior art (page 2, lines 7-11). EP’746 teaches that a major problem encountered in the use of radiolabeled antibodies to detect or treat tumors is the uptake or accumulation of radioactivity in the blood pool, in interstitial fluids, or in other tissues such as the liver and spleen (page 2, lines 28-30). EP’746 discloses that methods have been discovered for enhancing the biodistribution of antibodies specific for lesion-associated markers in mammalian subjects including the pretreatment of the subject with unlabeled antibody. At a time after initial exposure, the subject is again exposed to the same antibody. EP’746 teaches that the first exposure results in a decrease in the uptake of the subsequently administered labeled antibody by tissues such as the liver and spleen allowing for more of the subsequently administered antibody to remain in the blood and eventually reach the lesion site (page 3, lines 51-65).
EP’746 further teaches that it is also possible to increase the biodistribution by combining the pretreatment and treatment steps so as to administer the unlabeled and labeled antibody simultaneously (page 3, lines 56-59). EP’746 further teaches an example in which unlabeled and labeled antibody were injected simultaneously (page 12, example 5; page 13, lines 5-7).
EP’746 teaches a composition for use in therapy or diagnosis of lesions comprising a first amount of an antibody specific for a marker and a second amount of the same antibody, one of the said amounts of antibody being labelled with a detectable or therapeutic agent and the other being unlabeled, the said two amounts being for substantially simultaneous administration to the mammal (pages 15-16, claim 3).
Hagemann describes the preparation and use of a CD33 targeted thorium-277 conjugate for the treatment of acute myeloid leukemia. Hagemann conjugated a chelator to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling of the antibody with the alpha-emitter 227Th (the conjugate is referred to by Hagemann as “CD33-TTC” (abstract).
In Hagemann’s studies, animals were administered a single intravenous injection of CD33-TTC with radioactive doses of 500 kBq/kg - 700 kBq/kg and protein doses of 0.04 - 0.36 mg/kg (page 2424, left column, paragraphs 4 and 5; right column, paragraphs 1 and 2). Hagemann teaches that in vivo the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using a single dose regimen and that dose-dependent significant survival benefit was further demonstrated after administration of a single dose injection or a fractionated dose. Hagemann concludes that the data presented supports the further development of the CD33-TTC as a novel pharmaceutical treatment for AML (abstract).
Suey teaches that the future of nuclear medicine includes imaging and therapy with radiolabeled monoclonal antibodies (page 176, left column, paragraph 1). Suey further teaches that prior to treatment with the radioimmunoconjugate, patients receive an infusion of unlabeled monoclonal antibody. Small amounts of antibody, such as that present in the radioimmunoconjugate, may be removed rapidly from the blood and are localized nonspecifically to organs such as the liver. Larger dosages of unlabeled antibody, 10 to 100 times the amount present in the radioimmunoconjugate, may need to be infused as a preload to saturate nonspecific sites, allowing the subsequent dose of radiolabeled antibody to circulate sufficiently long so it can accumulate in the tumor (page 181, right column, paragraph 2).
As Suey teaches doses of unlabeled antibody that are 10 to 100 times the amount present in the radioimmunoconjugate, Suey is teaching ratios of 0.1:1 (which would be 1:10 labeled:unlabeled antibody) and 0.1:10 (which would be 1:100 labeled:unlabeled antibody). The ratio range disclosed by Suey overlaps with the range of the instant claim 30, rendering the claimed range obvious per MPEP 2144.05.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the method of Jurcic615 in which relapsed or refractory AML is treated with 225Ac-HuM195 at dosages of 0.5-4 uCi/kg to further administer daratumumab as disclosed by Dos Santos and further supported by Sanofi. It would have further been obvious to have labeled the daratumumab with 225Ac for administration at 0.5-4 uCi/kg based on the teachings of Jurcic615. It would have been obvious to administer unlabeled antibodies either sequentially or in simultaneously with the labeled antibodies in the same composition as taught by Ep’746 with concentrations of 0.4-3.6 mg/kg as suggested by Hagemann and Suey.
It would have been obvious to further administer daratumumab in the method of Jurcic615 as both Jurcic615 and Dos Santos are teaching the treatment of AML. MPEP 2144.06 states that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” The combination of antibodies targeting CD38 and CD33 is also supported by Sanofi which teaches antibodies specific for CD38 in the treatment of cancers including AML and teaches that such antibodies can be used in combination with additional therapeutics including CD33 antibodies (page 68, claim 69). Additionally, Dos Santos teaches that bone marrow blasts express CD33, further establishing both CD38 and CD33 as relevant targets in AML. An ordinarily skilled artisan would have had a reasonable expectation of success as both Jurcic615 and Dos Santos are teaching the treatment of AML and Sanofi also teaches the combination of CD38 antibodies with CD33 antibodies for treating cancers including AML.
An ordinarily skilled artisan would have been motivated to further label the daratumumab with 225Ac as Jurcic615 teaches that the labeling of antibodies with a radiolabel increases the antibody’s potency and teaches that 225Ac has a half-life of 10 days, yields 4 α-emitting isotopes, and can be conjugated to a variety of antibodies using DOTA-SCN. It would have been obvious to also use the dosages of 0.5-4 μCi/kg as Jurcic615 teaches that these are therapeutically relevant dosages of 225Ac when labeled to an antibody. An ordinarily skilled artisan would have had a reasonable expectation of success as Jurcic615 teaches that DOTA-SCN can be used to conjugate 225Ac to a variety of antibodies. Additionally, Dos Santos demonstrates that daratumumab efficiently targets CD28 expressing cells, including bone marrow blasts.
An ordinarily skilled artisan would have been motivated to administer unlabeled antibodies in addition to the labeled antibodies according to the teachings of EP’746 in order to enhance the biodistribution of the radiolabeled antibody in the subject as taught by EP’746. An ordinarily skilled artisan would have had a reasonable expectation of success as, like Jurcic615, EP’746 is concerned with the administration of radiolabeled antibodies for the treatment of cancers. The conclusion of obviousness for combining the labeled and unlabeled fractions into a single composition is further supported by KSR(E). See MPEP 2143. In this case, the use of unlabeled and labeled antibody fractions for increasing the biodistribution of radiolabeled antibodies and reducing the accumulation of the radiolabeled antibodies in undesired tissues, such as the liver and spleen, was known in the prior art. EP’746 demonstrates that it was known that the unlabeled antibody could either be administered before, or simultaneously in a single composition, with the radiolabeled antibody to achieve enhanced biodistribution. A person of ordinary skill in the art would have been able to pursue either of these known, potential solutions, with the reasonable expectation that the distribution of the labeled antibody to the lesion site would be enhanced and the accumulation in the radiolabeled antibody in undesired tissue would be reduced as taught by EP’746.
It would have been obvious to use unlabeled antibody concentrations of 0.4-3.6 mg/kg as Hagemann teaches that antibody concentrations of 0.04-0.36 mg/kg are therapeutically effective in targeting radiolabels to the desired tissue and Suey teaches that the unlabeled antibody administered should be at least 10 times the amount present in the radioconjugate. An ordinarily skilled artisan would have had a reasonable expectation of success as Hagemann and Suey are teaching clinically relevant antibody dosages for the treatment of cancer using labeled and unlabeled antibodies. The antibody concentration of 0.4-3.6 mg/kg falls within the claimed range of 0.01-5 mg/kg, rendering the claimed range obvious. See MPEP 2144.05.
Regarding claim 31, Jurcic615 teaches that the administration of 0.5-4 μCi/kg 225Ac-HuM195 in patients with relapsed or refractory AML resulted in a bone marrow blast reduction of ≥50% in 50% of subjects. As the administration of the radiolabeled HuM195 antibody alone was capable of achieving at least the claimed reduction in bone marrow blasts, an ordinarily skilled artisan would reasonably expect that the same reduction, or higher, could be achieved by including radiolabeled anti-CD38 antibody and delivering both antibodies in labeled and unlabeled fractions. This is particularly the case as the applied references suggest better biodistribution using labeled and unlabeled fractions, suggesting that more of the radiolabeled antibody will reach its target site.
Claims 26 and 29 is rejected under 35 U.S.C. 103 as being unpatentable over Jurcic , J.G., et al (2011) Abstract 615. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in acute myeloid leukemia (AML) Blood 118(21); 768 (herein “Jurcic615”) in view of Dos Santos, C., et al (2014) Abstract 616. Anti-Leukemic activity of daratumumab in acute myeloid leukemia cells and patient-derived xenografts Blood 124(21); 2312, US 2011/0262454 A1 (Sanofi-Aventis) 27 OCT 2011, EP 0337746 (Beatty, J.D. and B. G. Beatty) 18 OCT 1989, Hagemann, U.B., et al (2016) In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the treatment of Acute Myeloid Leukemia Mol Cancer Ther 15(10); 2422-2431, and Suey, C.M., et al. (1990) Radioimmunotherapy with Monoclonal antibodies Journal of Nuclear Medicine Technology 18(3) 176-183 as applied to claim 26 above, and in further view of Maguire, W.F., et al (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for α-particle radioimmunotherapy of cancer The Journal of Nuclear Medicine 55(9); 1492-1498.
The combination of Jurcic615, Dos Santos, Sanofi, EP’746, Hagemann, and Suey teach the method of claim 25 as discussed above.
As discussed in detail above, Suey suggests labeled to unlabeled antibody fractions that overlap with the range claimed in instant claim 29, rendering the claimed range obvious per MPEP 2144.05.
The applied references, however, do not disclose that the SCN-DOTA is pSCN-DOTA where the pSCN-DOTA is conjugated to the antibody and 225Ac is chelated to the DOTA-conjugated antibody.
Maguire teaches that targeted α-particle radiation using the radioisotope 225Ac is a promising form of therapy for various types of cancer. Maguire further teaches that historic obstacles to the use of 225Ac has been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies (abstract, introduction information). Maguire teaches methods in which antibodies were conjugated with DOTA and then radiolabeled the constructs in 1 chemical step. Maguire then characterized their stability, immunoreactivity, distribution, and therapeutic efficacy in healthy and tumor-bearing mice (abstract, methods). Maguire teaches that various chelators were investigated with many failing to chelate the metal at all and others appearing to radiolabel but then release 225Ac when subjected to serum. After testing various additional chelating strategies, Maguire achieved stable labeling with the chelator DOTA using a procedure in 2 steps designed to minimize radiolysis and maximize kinetic stability of the products. Maguire teaches that this procedure has since been used as a standard in several successful preclinical studies and is currently in human clinical trials in the form of 225Ac-HuM195 to treat advanced myeloid leukemias (page 1492, right column, paragraph 2). In the disclosure by Maguire, a 1 step labeling process is performed using the chelating agent p-SCN-Bn-DOTA (page 1493, left column, paragraph 3). The 225Ac-labeled HuM195 antibody produced by Maguire is the product of p-SCN-Bn-DOTA being conjugated to the antibody to form a DOTA-conjugated antibody (Figure 1, page 1493; page 1494, left column, paragraph 2, “p-SCN-Bn-DOTA… dissolved in water… was added to metal-free antibody”) followed by the chelating of the 225Ac radionuclide to the DOTA-conjugated antibody (page 1494, Figure 2, page 1494, left column, radiolabeling procedures”).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the method of conjugating the radioisotope 225Ac to antibodies taught by Maguire to generate the 225Ac-labelled HuM195 and 225Ac-labelled daratumumab for use in the method taught by Jurcic615, Dos Santos, Sanofi, EP’746, Hagemann, and Suey. An ordinarily skilled artisan would have been motivated to use the methods of Maguire to label the antibodies as Maguire teaches that they result in stable, therapeutically active conjugates of antibodies labeled with 225Ac with high specific activity (Maguire, abstract, conclusion). An ordinarily skilled artisan would have had a reasonable expectation of success as Maguire is teaching the labeling of the anti-CD33 antibody HuM195 with 225Ac. Additionally, a skilled artisan would reasonably expect that the method disclosed by Maguire could be used to label other antibodies with 225Ac, such as daratumumab.
Response to Arguments
Applicant’s arguments filed 11/01/2024 have been fully considered in so far as they apply to the rejections of the instant office action, but were not found to be persuasive.
With regards to the rejection of the claims under 35 USC 103, applicant argues that Sanofi does not establish any motivation to select CD33 from among the multitude of other therapeutic agents. Applicant argues that the therapeutic agents disclosed by Sanofi exceeds the finite number of predictable solutions with a reasonable likelihood of success as required for the obvious to try rationale relied upon.
Explicit motivation in the prior art is not required in order establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which (G) requires that there be some teaching, suggestion, or motivation in the prior art. With regards to the combination of HuM195 (an anti-CD33 antibody) and daratumumab (an anti-CD38 antibody), in the modified rejections of the instant office action relies upon KSR(A) and MPEP 2144.06 which states that combining two compositions separately taught by the art to be useful for the same purpose into a third composition to be used for the very same purpose is prima facie obvious.
In this case, both CD33 and CD38 were known targets for the treatment of AML and antibodies to these antigens had been studied and demonstrated in the prior art. As such, it would have been obvious to combine the antibodies into a third composition for the same use of treating subjects with AML. This combination is further supported by Sanofi, which suggests combining CD38 antibodies with other therapeutics including anti-CD33 antibodies. The newly applied reference Dos Santos, which studied daratumumab in the treatment of AML, teaches that bone marrow blasts express CD33 further demonstrating that both antigens were present in AML and could be targeted for treatment. It is shown that the prior art includes each antibody for AML although not necessarily in a single prior art reference, that one could have combined the antibodies in the treatment of AML, and that one would have recognized that the combination would have predictably been able to treat AML.
While applicant argues that Sanofi lists a multitude of other therapeutic agents, there is no set number to exceed for a finite number of solutions, as long as the solutions are predictable. Sanofi discloses other therapeutics but does so in a distinct manner such that each of the solutions could reasonably be pursued, including the combination with an anti-CD33 antibody, with a reasonable expectation of success in treating the cancers disclosed, which include AML. Applicant does not provide any substantial evidence to counter the conclusion of reasonable expectation of success or to demonstrate that the result of the claimed combination of targeting CD33 and CD38 together results in outcomes that could not have been predicted or are unexpected.
Additionally, applicant cites The Proctor & Gamble co., v. Teva Pharms as stating that where the art gives either no indication of which parameters are critical or no direction as to which of many choices is likely to be successful, the courts should not succumb to hindsight claims of obviousness. The citation further indicates that patents are not barred just because it was obvious to explore a new technology or general approach that seemed to be a promising field.
The case law cited by applicant, which is discussed in Example 10 of MPEP 2143 B regarding simple substitution, is concerned with a chemical compound in which obviousness was argued over similarities to a compound that was known in the prior art. In the case, the compound was not known in the prior art, but thirty-six other similar compounds were known and obviousness was argued over structural similarity.
In the instant case, both HuM195 and daratumumab were known in the prior art and had been demonstrated in the treatment of AML. As such, the obviousness rejection does not rely on general teachings or general approaches, but rather the combination of known elements leading to predictable results.
Applicant further argues that none of the cited references, alone or in combination, teach or reasonably suggest the combined administration of anti-CD33 and anti-CD38 antibody compositions each including an unlabeled and labeled fraction as required. Applicant argues that the rejection relies on hindsight reasoning.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
While none of the references alone individually teach the claimed method, the combination of the applied prior art demonstrate either that the elements were known in the prior art and could be combined to achieve a predictable outcome or that there was specific motivation to modify the prior art to arrive at the claimed combination.
For instance, as discussed above, HuM195 and daratumumab were known in the prior art as antibodies that could be used to treat AML and would have been obvious to combine. Jurcic615 teaches that radiolabeling antibodies increases the antibody’s potency yet avoids nonspecific cytotoxicity motivating the radiolabeling of antibodies with 225AC which has a long half-life, 4 α-emitting isotopes, and can be conjugated to a variety of antibodies using DOTA-SCN. EP’746 demonstrates that the administration of labeled and unlabeled fractions of antibodies, either sequentially or simultaneously, was known to enhance the distribution of the radiolabeled antibody. This is further supported by Suey which teaches that preloading to saturate nonspecific sites allows the subsequent dose of radiolabeled antibody to circulate sufficiently long such that it can accumulate at the tumor cite. Suey also teaches how much unlabeled antibody compared to labeled antibody should be administered to achieve such outcomes.
Based on these teachings, an ordinarily skilled artisan would have arrived at the instantly claimed invention with a reasonable expectation of success by following the teachings and suggestions of the prior art.
With regards to EP’746 (referenced in the response as Beatty), applicant argues that, while EP’746 mentions the possibility of simultaneous injection of labeled and unlabeled antibody, the purported mechanism of action to which E’746 attributes the benefit would lead a person of ordinary skill in the art towards sequential administration, not simultaneous.
As discussed in detail in the rejection, EP’746 teaches both sequential and simultaneous administration of labeled and unlabeled fractions in an effort to enhance biodistribution of a radiolabeled antibody. While applicant argues that an ordinarily skilled artisan would have been lead towards sequential administration, the teaching of alternative embodiments does not criticize, discredit, or otherwise discourage the claimed solution. See MPEP 2123 (II).
EP’746 explicitly states that it is also possible to increase biodistribution by combining the pretreatment and treatment steps so as to administer unlabeled and labeled antibody simultaneously (page 3, lines 51-59) demonstrating that EP’746 viewed simultaneous administration as a viable alternative to pretreatment for enhancing biodistribution. EP’746 also provides an example comparing sequential and simultaneous administration and antibody uptake in Example 5 for intravenous and intraperitoneal administration routes (pages 12-14) further demonstrating their alternative use.
Applicant further argues that EP’746 uses an antibody directed to CEA and demonstrates its use in models of colon cancer. Applicant argues that it is not explained why a person of ordinary skill in the art would have had a reasonable expectation of success using wholly unrelated cell types and antigens from those disclosed by EP’746.
While EP’746 studied a different antibody and cancer than that of the instantly claimed invention, an ordinarily skilled artisan would have nevertheless had a reasonable expectation of success in administering labeled and unlabeled antibody to enhance biodistribution as the principles taught by EP’746 would be expected to apply regardless of the cancer type or antigen that is targeted.
EP’746 teaches that a major problem encountered in the use of radiolabeled antibodies to detect or treat tumors is the uptake or accumulation of the radioactivity caused by the radiolabeled antibodies, fragments, or their metabolites, in the blood pool, interstitial fluids, or other tissues such as the liver and spleen (page 2, lines 28-30). If administered antibody is radiolabeled and there is a substantial amount of marker substance available in circulation, then antibody-antigen complexes formed will be cleared rapidly, primarily by the liver and spleen. Such uptake predominates over any uptake by tumor and significantly reduces the resolution of tumor location (page 2, lines 34-41). This issue is solved by EP’746 either through sequential or simultaneous administration of labeled and unlabeled antibody.
While EP’746 studied CEA antigen in colon cancer, the motivation behind the teachings of EP’746 would be expected to apply to other antigen targets/cancers. That is to say that systemic administration of a labeled antibody would be expected to form complexes with the antigen and subsequently be cleared by organs such as the liver and spleen. This is further supported by the teachings of Suey, which does not describe any particular antibody but still teaches that larger doses of unlabeled antibody infused preloads and saturates nonspecific sites allowing the subsequent radiolabeled antibodies to circulate longer to sufficiently accumulate at the tumor cite. These teachings of Suey demonstrate that the idea of administering labeled and unlabeled antibody was not exclusive to the CEA antigen and colon cancer studied by EP’746.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1616