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 .
Claims Status
Claims 2-3 and 5-7 are cancelled. Claim 52 is newly added. Claims 1, 8-25, and 52 are pending and are examined on the merits.
NEW/UPDATED REJECTIONS AS NECESSITATED BY CLAIM AMENDMENTS
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.
Claims 1, 8-14, and 23-25 remain rejected and Claim 52 is newly rejected under 35 U.S.C. 103 as being unpatentable over Nagorsen et al. 2012 (US 2012/0328618 A1; of record), herein “Nagorsen”, and in view of “BLINCYTO® (blinatumomab) for injection, for intravenous use” (FDA Reference ID: 4241595; Revision 03/29/2018; of record), herein “FDA”, and Hoelzer 2009 (Clin Adv Hematol Oncol, 7(11), 728-729; PTO-892), herein “Hoelzer”.
Regarding instant Claims 1, 10, 12, 25, and 52, Nagorsen teaches a method for treating malignant CD19-positive lymphoma or leukemia in a human patient (Pg. 16; claim 4) – including aggressive non-Hodgkin lymphoma such as Burkitt’s lymphoma (claim 37, ¶0087) – comprising administering intravenously (Pg. 16; claim 5) a first dose of a CD19xCD3 bispecific antibody for a first period of time followed by a second dose for a second period of time (Pg. 16; claim 2), wherein the second period of time exceeds the first period of time (Pg. 16; claim 8).
Nagorsen further states that the first period of time can be anywhere within the claimed range between 3 and 10 days, including 4 days (¶ 114). Nagorsen further teaches that the first dose is between 1 and 15 μg/m2/d (Pg. 16; claim 15) and the second dose is between 15 and 60 μg/m2/d (Pg. 16; claim 16), with 15 μg/m2/d for the first dose and 60 μg/m2/d for the second dose being “particularly preferred” (Pg. 8; ¶ 126 and ¶ 138).
Additionally, Nagorsen teaches that the second period of time is between 18 and 81 days, including a period of time of 24 days (¶118-120), and that the total time for a treatment cycle comprising a first and second dose level can be 28 days (e.g. Pg. 15, Example 6; 7 days at 15 μg/m2/d followed by 21 days at 60 μg/m2/d).
Regarding instant Claims 1 and 8-9, Nagorsen teaches that the dosage regimens taught therein can be repeated two, three, five or more times (i.e. a second, third, fifth etc. treatment cycle after completing a first; ¶0110).
Regarding instant Claims 13-14, Nagorsen teaches that the CD19xCD3 antibody is MT103 (Pg. 16; claim 2), which is a bispecific single-chain CD19xCD3 antibody also known as Blinatumomab (¶0007).
Although Nagorsen teaches that the first period of time corresponding to the first dose is between 3 and 10 days (Pg. 16; Claim 10), this is a broader limitation than a first period of time of 4 days, as recited in instant Claim 1 and required by all claims.
However, Nagorsen teaches that the step-up dose allows patients at higher risk of adverse reactions time to “adapt” to the treatment (¶ 115) and the first period of time “may be variable in view of, for example, the age, sex, body weight, etc. of the human patient” (¶ 117). Accordingly, the skilled artisan would have recognized that a first period of time of 3-10 days, including 4 days, taught by Nagorsen is subject to routine optimization according to the specific needs of a patient, and a first dose over a period of 4 days is an obvious variant of the treatment regimen taught by Nagorsen. One of ordinary skill in the art would have been motivated to choose a 4-day first dose based on several factors, including a positive response or noted tolerance to the treatment by the patient as well as the state of the disease and urgency with which a higher dose might be needed.
Further, although Nagorsen teaches that the second period of time corresponding to the second dose is between 18 and 81 days (¶119), this is a broader limitation than the 24 days as recited in instant Claim 1 and required by all claims.
However, Nagorsen teaches that “likewise the duration of the first period of time, the duration of the second period of time may be variable in view of for example, the age, sex, body weight, etc. of the human patient” (¶117), and further expressly states that a 24-day period is envisaged (¶120). Accordingly, the skilled artisan would have recognized that a second period of time of 18-81 days, including 24 days, taught by Nagorsen is subject to routine optimization according to the specific needs of a patient, and a second dose over a period of 24 days is an obvious variant of the treatment regimen taught by Nagorsen. One of ordinary skill in the art would have been motivated to choose a 24-day second dose, for example, to match the total treatment cycle of 28 days taught by Nagorsen (Example 6) in the context of a shorter 4-day initial dose level discussed above.
In addition, Regarding Claim 1, although Nagorsen teaches the treatment cycles can be repeated “in any event as often as there is a beneficial effect for a patient” (¶0110), Nagorsen is silent on when additional treatment cycles are initiated (i.e. “within 10 days after completing the first treatment cycle”, as required by Claim 1). This deficiency is cured by FDA and Hoelzer.
FDA teaches an FDA-approved treatment regimen for a CD19xCD3 antibody (blinatumomab) comprising multiple treatment cycles (§2; “DOSAGE AND ADMINISTRATION”). FDA teaches that a first treatment cycle is followed by a 14-day treatment-free period, followed by multiple additional cycles, each separated from the next by a 14-day treatment-free period.
FDA further teaches that there is no recovery of peripheral B-cells during the 2-week treatment-free period between cycles (Pg. 26, §12.2, ¶3), and that the half-life of blinatumomab is short (~2.1 hours) (Pg. 27; § Elimination).
Hoelzer teaches that the fast doubling time of Burkitt’s lymphoma provided a rationale for new aggressive treatment protocols, and that these newer regimens incorporated “only short intervals” between treatment cycles “to avoid recovery of the malignant cell population” (Pg. 728, Col. 2, ¶1-3).
Hoelzer further suggests that CD19-directed immunotherapies such as blinatumomab/MT-103 could be a promising treatment option for Burkitt’s lymphoma (Pg. 729, last ¶).
It would have been obvious to one of ordinary skill in the art to incorporate a treatment-free period between the first and subsequent treatment cycles taught by FDA into the method of treatment taught by Nagorsen (summarized above) wherein the treatment-free period is modified to be shortened, for example, to 10 or fewer days. The skilled artisan would have been motivated to shorten this treatment-free period in view of the teachings of Hoelzer, which highlights the fast-growing nature of Burkitt’s lymphoma and teaches that recent successes in treating this aggressive disease incorporated “only short intervals” between treatment cycles “to avoid recovery of the malignant cell population”, and suggests blinatumomab as a promising treatment option for Burkitt’s lymphoma.
There would have been a reasonable expectation of success because FDA teaches that there was no recovery of B cells during the 14-day treatment-free period – indicating recovery would be even less likely with a shorter period of time. In addition, because FDA teaches that the half-life of blinatumomab is very short, the skilled artisan would recognize that the treatment-free period could be shortened further while still allowing adequate time for the previously administered therapeutic to be cleared from the patient’s system prior to subsequent treatment cycles. Moreover, Nagorsen teaches the treatment cycles can be repeated “in any event as often as there is a beneficial effect for a patient”, and the particular length of time (e.g. 5, 6, or 10 days, etc.) between treatment cycles in the modified protocol would be subject to routine optimization according to the particular needs of the patient population, their response to the treatment, and the observed B cell counts during the treatment free interval.
Instant Claim 11 is drawn to the method of Claim 1 (summarized above) wherein the Burkitt’s lymphoma is relapsed or refractory.
The combined teachings of Nagorsen, FDA, and Hoelzer are silent on whether the Burkitt’s lymphoma is relapsed or refractory.
However, Nagorsen further discloses that Blinatumomab, a CD19xCD3 bispecific antibody, displays a high rate and duration of responses when used to treat patients with relapsed non-Hodgkin lymphoma (NHL) and B-precurser acute lymphocytic leukemia (ALL) (Example 1; ¶0237). It would therefore have been obvious to one of ordinary skill in the art that the treatment regimen taught by Nagorsen could be applied to patients wherein the leukemia is relapsed. The skilled artisan would have been motivated to do so because Nagorsen teaches that this particular treatment regimen can reduce the risk of adverse effects of the treatment (Abstract). Further, the skilled artisan would have had a reasonable expectation of success given prior successes in treating relapsed NHL and ALL with a CD19xCD3 antibody (Example 1; ¶0237).
Instant Claim 23 is drawn to the method of Claim 1 (summarized above) wherein treatment results in a MRD negative status of the Burkitt’s lymphoma patient.
Nagorsen, FDA, and Hoelzer are silent on whether the treatment results in a MRD negative status for the Burkitt’s lymphoma patient. However, the active steps of performing the method of the combined teachings of Nagorsen, FDA, and Hoelzer and those of the instant claims are the same, and therefore, absent evidence to the contrary, the method of Nagorsen would have been inherently capable of producing the same result.
Further, one of ordinary skill in the art would have recognized MRD negative status as an obvious goal, endpoint, or result of the specific CD19xCD3 treatment regimen taught by Nagorsen, FDA, and Hoelzer given that Nagorsen further teaches that minimal residual disease (MRD) refers to the small number of leukemic/lymphoma cells remaining after a treatment when the patient is in remission (¶0124). The skilled artisan would have a reasonable expectation of success given that prior treatment regimens involving CD19xCD3 bispecific antibodies could eliminate MRD (¶0123).
Instant Claim 24 is drawn to the method of Claim 1 (summarized above) wherein the patient is characterized by a B:T cell ratio of less than 1:8.
Although Nagorsen teaches a CD19xCD3 treatment regimen wherein the patient is characterized by a B:T cell ratio of less than 1:5 (Pg. 16; claim 2), this is a broader range than required by the instant claims.
However, Nagorsen teaches that a B:T ratio of <1:10 is a cut off for development of adverse neurological events (¶0253), and patient characterized by a ratio of less than 1:8 is among the preferred embodiments (¶0058).
One of ordinary skill in the art would have therefore recognized a B:T ratio of 1:5 or less as conservative threshold for implementing the step-up dosing regimen taught by Nagorsen, and it would have been obvious that a ratio of 1:8 is acceptable as an alternative threshold for implementing this treatment method. The skilled artisan would have a reasonable expectation of success given that a B:T of 1:8 is close to, but still greater than, the 1:10 cut off for developing adverse neurological events taught by Nagorsen.
Claims 15-22 remain rejected under 35 U.S.C. 103 as being unpatentable over Nagorsen et al. 2012 (US 2012/0328618 A1; of record), herein “Nagorsen”, “BLINCYTO® (blinatumomab) for injection, for intravenous use” (FDA Reference ID: 4241595; Revision 03/29/2018; of record), herein “FDA”, and Hoelzer 2009 (Clin Adv Hematol Oncol, 7(11), 728-729; PTO-892), herein “Hoelzer”, as applied to Claim 1 above, and further in view of Kufer et al. 2014 (US 2014/0227272 A1; of record), herein “Kufer”.
Claims 15-22 are drawn to the method of Claim 1 (summarized above) further comprising administering PPS prior to the first and second dose of CD19xCD3 antibody of each treatment cycle (Claim 15), wherein the PPS is administered 2-24 hours prior to each dose (Claim 16), and administration is continued for 7 consecutive days after administration of the first CD19xCD3 dose (Claims 17-18). Claims 19-21 further specify the dose as 300mg/day administered in 3 doses of 100mg, and Claim 22 specifies the PPS can be administered orally. The period of consecutive treatment days specified by Claims 17-18 are interpreted to begin shortly after the administration of a CD19xCD3 dose begins and continue concurrently with the period of time over which said dose is administered.
The teachings of Nagorsen, FDA, and Hoelzer are summarized above.
Regarding Claims 15-22, the combination of Nagorsen, FDA, and Hoelzer fails to teach the use of PPS in combination with CD19xCD3 therapy or the specific regimens detailed therein. However, these deficiencies are cured by Kufer.
Kufer teaches a method of reducing adverse neurological events correlated with treatment of B-cell malignancies by the CD19xCD3 bispecific antibody MT103 (¶0005-0013; “BACKGROUND OF THE INVENTION”) comprising administering pentosanpolysulfate (PPS) prior to, concurrently with, or subsequent to CD19xCD3 therapy (¶0200). Kufer further teaches that PPS can be administered orally at a dose of 100mg three times per day, and that PPS can be administered 24 hours preceding CD19xCD3 therapy followed by continued administration over 72 hours (¶0199).
Because Nagorsen teaches that a patient with a B:T cell ratio lower than 1:5 are at higher risk for adverse neurological reactions to CD19xCD3 antibody therapy (¶0021), one of ordinary skill in the art would have been motivated to combine the PPS co-treatment taught by Kufer with the CD19xCD3 regimen according to the combined teachings of Nagorsen, FDA, and Hoelzer in order to reduce the risk of such adverse events in the treatment of patients with Burkitt’s lymphoma.
Further, the PPS regimen taught by Kufer (24 hours before a dose, followed by 72 hours), when combined with the CD19xCD3 regimen taught by Nagorsen (a first and second dose separated by 4 days), results in PPS treatment for 7 consecutive days after the first CD19xCD3 dose (72 hours + 24 hours + 72 hours), as claimed in Claim 18.
Combining the teachings of Kufer and Nagorsen would have been obvious and one of ordinary skill would have had a reasonable expectation of success given the explicit suggestion by Kufer ¶0244 that "[o]ther treatment regimens which are envisaged in the context of the present invention are disclosed in PCT/EP2010/066207” (Note: PCT/EP2010/066207 comprises the same disclosure as the “Nagorsen” US 2012/0328618 A1 reference relied upon in this rejection).
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive.
Claim 1 has been amended to require a 28-day treatment cycle wherein a first dose is administered for a period of time of 4 days and a second dose is administered for the remaining 24 days. The rejections above rely on the same references as previously applied and have been updated to reflect the new scope of the claims.
Briefly, Nagorsen teaches a method of treating B-cell cancers with CD19xCD3 antibody blinatumomab comprising a first dose of 15 μg/m2/d for a first period of time between 3 and 10 days and followed immediately by an increased 60 μg/m2/d for an additional 18 to 81 days. Moreover, Example 6 of Nagorsen establishes a 28-day treatment cycle comprising the same first (15 μg/m2/d) and second (60 μg/m2/d) doses, differing from the instant claims only in that escalation from the lower 15 μg/m2/d dose to the higher 60 μg/m2/d dose takes place after 7 days instead of only 4 days. However, the first period of time (4 days), second period of time (24 days), and treatment cycle length each fall within the ranges envisaged by Nagorsen, and Nagorsen teaches the particular values for each of these periods of time may vary according to the specific needs of a patient. Discovery of the “optimal” dosing/intervals within the ranges taught by the prior art constitutes “routine optimization” well within the purview of one of ordinary skill in the art and can vary according to patient disposition and disease state (See MPEP 2144.05 (II)).
Applicant further argues that “Hoelzer is not relevant as it relates to a completely different therapy for treating Burkitt lymphoma or leukemia”. However, Hoelzer was not relied upon to teach the particulars of the claimed treatment method. Instead, Hoelzer speaks to the general understanding in the art that Burkitt lymphoma is an especially aggressive form of cancer which warrants modifications to existing treatment protocols, such as shortening the interval between treatment cycles to avoid recovery of the malignant cell population. Accordingly, the skilled artisan would have been motivated by the teachings of Hoelzer regarding the rapid growth of Burkitt’s lymphoma and strategies of treating said cancer with a more intensive protocol to modify the treatment regimen taught by Nagorsen and FDA. The particular change from treatment-free interval of the prior art (14 days) to that of the instant claims (10 days or fewer) could be arrived at by routine optimization by one of ordinary skill in the art.
Finally, to the extent that Applicant appears to argue unexpected results/efficacy of the claimed treatment method (e.g. “this was the first case in which the high dose of antibody...was reached so fast” and “Such rapid response to treatment had never been observed before at that therapeutic dose in Non Hodgkin Lymphoma (NHL)”; Remarks, Pg. 8), it is noted that the invention as claimed does not require all the elements with which those results were achieved. Notably, all but Claim 14 are drawn to a generic “CD19xCD3 bispecific antibody” whereas the antibody of the examples blinatumomab (Spec ¶00213). In addition, the treatment method of Example 1 included a regimen of 300mg/day dose of pentosane polysulfate (PPS) to control the neurological toxicity of blinatumomab (¶00214), which presumably contributed to the success in safely achieving the rapid dose escalation. As such, the claims are not commensurate in scope with any of the purportedly unexpected results.
Double Patenting
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.
Claims 1, 8-14, and 23-25 remain rejected and Claim 52 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 7-15 of U.S. Patent No. 8,840,888 in view of Nagorsen et al. 2012 (US 2012/0328618 A1; of record), herein “Nagorsen”, “BLINCYTO® (blinatumomab) for injection, for intravenous use” (FDA Reference ID: 4241595; Revision 03/29/2018; of record), herein “FDA”, and Hoelzer 2009 (Clin Adv Hematol Oncol, 7(11), 728-729; PTO-892), herein “Hoelzer”.
Regarding instant Claims 1-3, 5-10, 12-14, and 25, ‘888 claims 1 and 3-4 are drawn a method for treating malignant CD19-positive leukemia or lymphoma cells in a human patient comprising administering intravenously a first dose of MT103 (a bispecific single-chain CD19xCD3 antibody) for a first period of time followed by a second dose for a second period of time, wherein the second dose exceeds the first dose. ‘888 claims 7-15 are further drawn to a method wherein the second period of time exceeds the first period of time, wherein said first period of time is between 3-10 days and the second period of time is 18 to 81 days, and wherein the first dose is between 1 and 15 μg/m2/d and the second dose is between 15 and 60 μg/m2/d.
The claims of ‘888 are not drawn to the specific first and second dose of 15 μg/m2/d and 60 μg/m2/d, respectively, a first period of time consisting specifically of 4 days, a second period of time consisting specifically of 24 days, or additional treatment cycles. These deficiencies are cured by Nagorsen.
Regarding instant Claims 1, 10, 12, 25, and 52, Nagorsen teaches a method for treating malignant CD19-positive lymphoma or leukemia in a human patient (Pg. 16; claim 4) – including aggressive non-Hodgkin lymphoma such as Burkitt’s lymphoma (claim 37, ¶0087) – comprising administering intravenously (Pg. 16; claim 5) a first dose of a CD19xCD3 bispecific antibody for a first period of time followed by a second dose for a second period of time (Pg. 16; claim 2), wherein the second period of time exceeds the first period of time (Pg. 16; claim 8).
Nagorsen further states that the first period of time can be anywhere within the claimed range between 3 and 10 days, including 4 days (¶ 114). Nagorsen further teaches that the first dose is between 1 and 15 μg/m2/d (Pg. 16; claim 15) and the second dose is between 15 and 60 μg/m2/d (Pg. 16; claim 16), with 15 μg/m2/d for the first dose and 60 μg/m2/d for the second dose being “particularly preferred” (Pg. 8; ¶ 126 and ¶ 138).
Additionally, Nagorsen teaches that the second period of time is between 18 and 81 days, including a period of time of 24 days (¶118-120), and that the total time for a treatment cycle comprising a first and second dose level can be 28 days (e.g. Pg. 15, Example 6; 7 days at 15 μg/m2/d followed by 21 days at 60 μg/m2/d).
Regarding instant Claims 1 and 8-9, Nagorsen teaches that the dosage regimens taught therein can be repeated two, three, five or more times (i.e. a second, third, fifth etc. treatment cycle after completing a first; ¶0110).
Regarding instant Claims 13-14, Nagorsen teaches that the CD19xCD3 antibody is MT103 (Pg. 16; claim 2), which is a bispecific single-chain CD19xCD3 antibody also known as Blinatumomab (¶0007).
Although the claims of ‘888 require that the first period of time corresponding to the first dose is between 3 and 10 days (Pg. 16; Claim 10), this is a broader limitation than a first period of time of 4 days, as recited in instant Claim 1 and required by all claims.
However, Nagorsen teaches that the step-up dose allows patients at higher risk of adverse reactions time to “adapt” to the treatment (¶ 115) and the first period of time “may be variable in view of, for example, the age, sex, body weight, etc. of the human patient” (¶ 117). Accordingly, the skilled artisan would have recognized that a first period of time of 3-10 days, including 4 days, taught by Nagorsen is subject to routine optimization according to the specific needs of a patient, and a first dose over a period of 4 days is an obvious variant of the treatment regimen of the claims of ‘888. One of ordinary skill in the art would have been motivated to choose a 4-day first dose based on several factors, including a positive response or noted tolerance to the treatment by the patient as well as the state of the disease and urgency with which a higher dose might be needed.
Further, although the claims of ‘888 require that the second period of time corresponding to the second dose is between 18 and 81 days, this is a broader limitation than the 24 days as recited in instant Claim 1 and required by all claims.
However, Nagorsen teaches that “likewise the duration of the first period of time, the duration of the second period of time may be variable in view of for example, the age, sex, body weight, etc. of the human patient” (¶117), and further expressly states that a 24-day period is envisaged (¶120). Accordingly, the skilled artisan would have recognized that a second period of time of 18-81 days, including 24 days, taught by Nagorsen is subject to routine optimization according to the specific needs of a patient, and a second dose over a period of 24 days is an obvious variant of the treatment regimen according to the claims of ‘888. One of ordinary skill in the art would have been motivated to choose a 24-day second dose, for example, to match the total treatment cycle of 28 days taught by Nagorsen (Example 6) in the context of a shorter 4-day initial dose level discussed above.
In addition, the claims of ‘888 are not drawn to a second treatment cycle that begins “by 10 days after completing the first”, as required by all instant claims. This deficiency is cured by FDA and Hoelzer.
FDA teaches an FDA-approved treatment regimen for a CD19xCD3 antibody (blinatumomab) comprising multiple treatment cycles (§2; “DOSAGE AND ADMINISTRATION”). FDA teaches that a first treatment cycle is followed by a 14-day treatment-free period, followed by multiple additional cycles, each separated from the next by a 14-day treatment-free period.
FDA further teaches that there is no recovery of peripheral B-cells during the 2-week treatment-free period between cycles (Pg. 26, §12.2, ¶3), and that the half-life of blinatumomab is short (~2.1 hours) (Pg. 27; § Elimination).
Hoelzer teaches that the fast doubling time of Burkitt’s lymphoma provided a rationale for new aggressive treatment protocols, and that these newer regimens incorporated “only short intervals” between treatment cycles “to avoid recovery of the malignant cell population” (Pg. 728, Col. 2, ¶1-3).
Hoelzer further suggests that CD19-directed immunotherapies such as blinatumomab/MT-103 could be a promising treatment option for Burkitt’s lymphoma (Pg. 729, last ¶).
It would have been obvious to one of ordinary skill in the art to incorporate a treatment-free period between the first and subsequent treatment cycles taught by FDA into the method of treatment taught by the claims of ‘888 in view of Nagorsen (summarized above) wherein the treatment-free period is modified to be shortened, for example, to 10 or fewer days. The skilled artisan would have been motivated to shorten this treatment-free period in view of the teachings of Hoelzer, which highlights the fast-growing nature of Burkitt’s lymphoma and teaches that recent successes in treating this aggressive disease incorporated “only short intervals” between treatment cycles “to avoid recovery of the malignant cell population”, and suggests blinatumomab as a promising treatment option for Burkitt’s lymphoma.
There would have been a reasonable expectation of success because FDA teaches that there was no recovery of B cells during the 14-day treatment-free period – indicating recovery would be even less likely with a shorter period of time. In addition, because FDA teaches that the half-life of blinatumomab is very short, the skilled artisan would recognize that the treatment-free period could be shortened further while still allowing adequate time for the previously administered therapeutic to be cleared from the patient’s system prior to subsequent treatment cycles. Moreover, Nagorsen teaches the treatment cycles can be repeated “in any event as often as there is a beneficial effect for a patient”, and the particular length of time (e.g. 5, 6, or 10 days, etc.) between treatment cycles in the modified protocol would be subject to routine optimization according to the particular needs of the patient population, their response to the treatment, and the observed B cell counts during the treatment free interval.
Regarding instant Claim 11, Although ‘888 claim 3 is drawn to a treatment regimen for leukemia, it is silent on whether the leukemia is relapsed or refractory.
However, Nagorsen discloses that Blinatumomab, a CD19xCD3 bispecific antibody, displays a high rate and duration of responses when used to treat patients with relapsed non-Hodgkin lymphoma (NHL) and B-precurser acute lymphocytic leukemia (ALL) (Example 1; ¶ 237). It would therefore have been obvious to one of ordinary skill in the art that the treatment regimen of ‘888 could be applied to patients wherein the leukemia is relapsed. The skilled artisan would have been motivated to do so because Nagorsen teaches that this particular treatment regimen can reduce the risk of adverse effects of the treatment (Abstract). Further, the skilled artisan would have had a reasonable expectation of success given prior successes in treating relapsed NHL and ALL with a CD19xCD3 antibody (Nagorsen; Example 1; ¶ 237).
Regarding instant Claim 23, the claims of ‘888 are not drawn to a treatment regimen that results in a MRD negative status for the patient.
However, the active steps of performing the method of ‘888 and those of the instant claims are the same, and therefore, absent evidence to the contrary, the method of ‘888 would have been inherently capable of producing the same result. Further, one of ordinary skill in the art would have recognized MRD negative status as an obvious goal, endpoint, or result of the specific CD19xCD3 treatment regimen of ‘888 given that Nagorsen teaches that minimal residual disease (MRD) refers to the small number of leukemic cells remaining after a treatment when the patient is in remission (¶ 124). The skilled artisan would have had a reasonable expectation of success given that prior treatment regimens involving CD19xCD3 bispecific antibodies could eliminate MRD (¶ 123).
Regarding instant Claim 24, ‘888 claim 1 is drawn a method of treating wherein the patient is characterized by a B:T ratio of “about 1:5 or lower”, which is broader than the B:T ratio required by instant Claim 18.
However, Nagorsen teaches the same method as ‘888 and further discloses that a B:T ratio of <1:10 is a cut off for development of adverse neurological events (¶ 253), and patient characterized by a ratio of less than 1:8 is among the preferred embodiments (¶ 58). One of ordinary skill in the art would have therefore recognized a B:T ratio of 1:5 or less as conservative threshold for implementing the step-up dosing regimen taught by ‘888, and it would have been obvious that a ratio of 1:8 is acceptable as an alternative threshold for implementing this treatment method. The skilled artisan would have a reasonable expectation of success given that Nagorsen teaches a B:T of 1:8 is close to, but still greater than, the 1:10 cut off for developing adverse neurological events.
Claims 15-22 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 7-15 of U.S. Patent No. 8,840,888 in view of Nagorsen et al. 2012 (US 2012/0328618 A1; of record), herein “Nagorsen”, “BLINCYTO® (blinatumomab) for injection, for intravenous use” (FDA Reference ID: 4241595; Revision 03/29/2018; of record), herein “FDA”, and Hoelzer 2009 (Clin Adv Hematol Oncol, 7(11), 728-729; PTO-892), herein “Hoelzer”, as applied to Claim 1 above, and further in view of Kufer et al. 2014 (US 2014/0227272 A1; of record), herein “Kufer”.
Instant Claims 15-22 are summarized above.
The claims of ’888 are not drawn to a method of CD19xCD3 therapy further comprising administering PPS according to the dosing, schedule, and administration route of the instant claims. However, these claims are rendered obvious by Nagorsen and Kufer.
Kufer teaches a method of reducing adverse neurological events correlated with treatment of B-cell malignancies by the CD19xCD3 bispecific antibody MT103 (¶ 5-13; “BACKGROUND OF THE INVENTION”) comprising administering pentosanpolysulfate (PPS) prior to, concurrently with, or subsequent to CD19xCD3 therapy (¶ 200). Kufer further teaches that PPS can be administered orally at a dose of 100mg three times per day, and that PPS can be administered 24 hours preceding CD19xCD3 therapy followed by continued administration over 72 hours (¶ 199).
Additionally, Kufer teaches that "[o]ther treatment regimens which are envisaged in the context of the present invention are disclosed in PCT/EP2010/066207” (¶ 244). The disclosure of PCT/EP2010/066207 is the same as that taught by Nagorsen.
Given the explicit suggestion by Kufer that its teachings can be applied in the same context as the CD19xCD3 treatment regimen taught by Nagorsen, it would have been obvious to one of ordinary skill in the art to further modify the CD19xCD3 treatment regimen of ‘888 to include the PPS dosing and route of administration taught by Kufer. Accordingly, the PPS regimen taught by Kufer (24 hours before a dose, followed by 72 hours), when combined with the CD19xCD3 regimen taught by Nagorsen (a first and second dose separated by 4 days), results in PPS treatment for 7 consecutive days after the first CD19xCD3 dose (72 hours + 24 hours + 72 hours), as claimed in Claim 18. One would have had a reasonable expectation of success given that both the invention of ‘888 and the teachings of Kufer are drawn to methods of reducing adverse neurological events associated with CD19xCD3 bispecific antibody therapy.
Response to Arguments – Double Patenting
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive.
Regarding the double patenting rejections, Applicant cites the same arguments applied to the 103 obviousness rejections addressed above. Accordingly, the response to these arguments is the same.
Briefly, the Nagorsen reference comprises the same disclosure as Patent 8,840,888, and the combination of references (Nagorsen, FDA, and Hoelzer) provides motivation and a reasonable expectation of success to modify the 14-day treatment free period taught by FDA to instead comprise a shorter period of 10 or fewer days in view of the aggressive nature of Burkitt’s lymphoma, the suggestion in the prior art that protocols for treating Burkitt’s lymphoma comprise short intervals between treatment cycles, and the known pharmacokinetics of blinatumomab which result in rapid systemic clearance and would enable a shorter treatment-free interval.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643