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 .
Status of Claims
Claims -----1-18, 20-21, 23-24, 26-29, 31-32, 34-35, 37-40, 47-53, and 67-70 are currently pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The claims have an earliest effective filing date of 09/10/2020 corresponding to application PRO 63/076,765.
Information Disclosure Statement
The Information Disclosure Statements filed on 03/23/2026 and 03/23/2026 have been considered.
Response to Remarks filed 03/23/2026
Applicant’s amendments and arguments regarding the 35 USC 112 rejection have been fully considered and are persuasive. Specifically, addition of the VH and VL sequences of the biosimilar overcome the rejection. Therefore, the 35 USC 112 rejection is withdrawn.
Applicant’s amendments and arguments regarding the 35 USC 103 rejections have been fully considered and are not persuasive.
Specifically, Applicant states:
“Lignon is relied on as allegedly teaching the use of intravenous rituximab at 375 mg/m2, dexamethasone 40 mg/day, cytarabine 2 g/m2, and oxaliplatin 100 g/m2 (R-DHAX) in DLBCL patients in 21-day cycles. The Office acknowledges that Lignon fails to teach or suggest the use of subcutaneous epcoritamab to treat DLBCL, and relies on Lugtenburg to address this deficiency. Lugtenburg is relied on as allegedly teaching the use of subcutaneous epcoritamab to treat DLBCL in 28-day cycles. It would have been obvious for a skilled artisan to have combined the teachings of Lignon and Lugtenburg to arrive at a method of treating DLBCL with epcoritamab and R-DHAX/C administered in 21-day cycles until complete response, partial response, stable disease, or progressive disease. Moreover, the administration dosing and schedules recited in the claims are a matter of routine optimization.
Applicant respectfully traverses the rejection. From the outset, Applicant asserts that the Office has failed to establish even a prima facie case of obviousness because, even if the cited references were combined in the manner suggested by the Office, they would not result in the presently claimed methods. In addition, the pending claims are not obvious over the cited references at least because (1) there was no teaching or suggestion in the art that would have motivated the skilled artisan to combine epcoritamab with rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin, (2) combination treatment using cancer therapeutics were known in the art to be unpredictable, and (3) the claimed treatment regimen is associated with unexpected beneficial therapeutic effects which could not have been predicted based on the teachings of the cited references. Nothing in the combined teachings of Lignon and Lugtenburg would have led the skilled artisan to modify Lignon's methods in the manner suggested by the Office to arrive at the claimed methods, let alone with a reasonable expectation of success, as discussed below.”
The arguments set forth by the Applicant are not persuasive. Combining known cancer treatments for the purposes of treating the same cancer is obvious. One of ordinary skill in the art would expect addition of more drugs to a combination would achieve better results and therefore obvious to combine known treatments together and optimizing the dosage is common in the art.
Applicant further states:
“Even if, arguendo, Lignon was taken as a starting point in the manner suggested by the Office, a major concern to the skilled artisan when seeking to improve the combination of rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin by adding an additional antibody would have been whether any of the components would affect the mechanism of action of the added antibody (e.g., epcoritamab).
At the effective filing date of the present application, the lack of predictability pertaining to combination therapies involving immunotherapeutics was well-known based on frequent unforeseen complications or adverse effects (e.g., on safety and/or efficacy profiles). Simple mechanistic descriptions of how the pharmacological effects of two or more cancer therapeutics combine to provide the resultant effect is often impossible, particularly as the individual therapies often do not have the same target. Indeed, each cancer therapeutic may potentially affect downstream signaling pathways, not all of which are known and/or understood. For example, the interactions of therapeutics may lead to a variety of effects ranging from having no effect on each other (no interaction), to a greater than expected result (synergy), or a result that is less than the sum of the individual effects (antagonism).
As discussed in a review article by Henricks et al. (Cancer Treatment Reviews 41:859-867, 2015; Appendix A), many combination therapies containing antibodies led to detrimental effects, which were thought to be due to (1) excessive toxicity; (2) negative interaction between different signaling pathways; and (3) off-target pharmacodynamic interaction (see, page 864, 2"d column). The authors conclude that even when antibodies are theoretically suitable for use in combination therapy, the efficacy of particular combinations is not predictable.
Given this backdrop, nothing within the combined teachings of Lignon and Lugtenburg would have motivated the skilled artisan to modify the teachings of these references in the manner asserted by the Office. Rather, the skilled artisan would have been faced with myriad of choices for which immunotherapeutic to administer, at what dosages and administration cycles, and with what additional chemotherapeutic agent. Nor would there have been a reasonable expectation that the presently claimed method would be successful. See, e.g., Novartis Pharms. Corp. v. West- Ward Pharms. Int'l Ltd., No. 2018-1434, 2019 WL 2079879, *7-8 (Fed. Cir. May 13, 2019) where the court found that, despite a motivation to pursue the claimed method of treatment, such treatment would not have been obvious because the prior art did not show a sufficient expectation of success.
Epcoritamab targets B-cell antigen CD20 and the T-cell antigen CD3, thus facilitating T-cell mediated cytotoxicity of CD20 expressing malignant cells. In contrast, rituximab, the "R" component of R-DHAX/C, is a monospecific CD20 antibody with a mechanism of action that differs entirely from that of an anti-CD3xCD20 antibody such as epcoritamab. The effects of rituximab involve induction of cytotoxicity through Fc mediated effector functions such as antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. Given this major difference in mechanism of action between rituximab and epcoritamab, the finding that rituximab can be combined with dexamethasone, cytarabine, and oxaliplatin does not create a reasonable expectation of success that epcoritamab could likewise be combined with dexamethasone, cytarabine, and oxaliplatin.”
Applicant further states:
“A general unsupported assertion that the claimed invention was the result of "routine optimization" is insufficient to establish obviousness. The Patent Trial and Appeal Board of the United States Patent and Trademark Office (hereinafter "PTAB") has confirmed that obviousness cannot be established based on an unsupported allegation that a therapeutic invention is the result of "routine optimization", given the unpredictable and complex nature of therapeutics. For example, in Swiss Pharma International AG v. Biogen IDEC (IPR2016-00915, October 20, 2016; "Swiss Pharma"), the PTAB rejected Swiss Pharma's argument that Biogen's patent claims directed to a particular high concentration formulation of a humanized monoclonal antibody (natalizumab) were merely a "routine optimization" of known antibody formulations, since the prior art did not "suggest the desirability or need for a higher...concentration" and could not be "extrapolated" to the antibody in the claimed formulation. Similarly, in Coherus Biosciences Inc., v. Abbvie Biotechnology Ltd. (IPR2016-01018, November 7, 2016; "Coherus"), the PTAB rejected Coherus' argument that Abbvie's patent claims directed to a particular stable liquid aqueous pharmaceutical formulation were obvious, since Coherus did not sufficiently demonstrate "that a skilled artisan-without the benefit of hindsight-would have combined [prior art references] to achieve the claimed formulation with a reasonable expectation of success."
Analogous to the rationale of the PTAB as set forth in Swiss Pharma and Coherus, the presently claimed dosage regimen cannot be considered a result of "routine optimization." For instance, the Office has not provided any support that the prior art suggested the desirability or need for the presently claimed dosage regimen (e.g., a combination of epcoritamab and R-DHAX/C in 21-day cycles), nor has the Office demonstrated, without the benefit of hindsight as discussed above, that the skilled artisan would have combined the teachings of Lignon and Lugtenburg to achieve the claimed method with a reasonable expectation of success. Nor could it have been predicted, reasonably expected, or extrapolated from the combined teachings of Lignon and Lugtenburg that the presently claimed dosage regimen of epcoritamab and rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin would be both safe and effective. A general unsupported assertion that the claimed invention was the result of "routine optimization" is insufficient to establish obviousness (see Swiss Pharma and Coherus). In fact, it is clear from the Federal Circuit's decision in In re Stepan Co., No. 2016-1811 (Fed. Cir. Aug. 25, 2017) that the Office cannot shift the burden of proving patentability to the applicant and must provide reasons why one skilled in the art would arrive at the claimed invention and would have a reasonable expectation of success. Here, the Federal Circuit reversed the PTAB decision affirming an obviousness rejection based on routine optimization. In addition, as further noted by the Federal Circuit:
A further point regarding so-called "routine testing" is that § 103 provides that "[p]atentability shall not be negated by the manner in which the invention was made." 35 U.S.C. § 103 (2012). That provision was enacted to ensure that routine experimentation does not necessarily preclude patentability..... Here we are concerned with the question of whether the claimed would have been obvious at the time it was made to a person having ordinary skill in the art-not how it was achieved." (Honeywell International, Inc. v. Mexichem Amanco Holdings S.A. DE C.V. Fed. Cir. 2016-1996, Aug 1, 2017. Slip op at 13).”
Applicant’s arguments regarding unpredictability and routine optimization have been considered and are not persuasive. Regarding unpredictability, it is true that the art has established that when combining therapies issues involving efficacy, mechanism of action, and cytotoxicity may arise. The unpredictability affiliated with combining therapies is the exact reason it is predictable in the art to routinely optimize dosage when combining therapies. See MPEP 2144.06. “it is prima facie obvious to combine two (or more) compositions, each taught by the prior art to be useful for the same purpose, in order to achieve a single composition".
Therefore, it would be obvious to one of ordinary skill in the art to combine Lignon and Lugtenbur because Lignon et al teach successful treatment of DLBLC with intravenous rituximab at 375mg/m2, dexamethasone 40mg/ day, cytarabine 2g/m2, and oxaliplatin 100g/m2 (RDHAX) in DLBLC patients in 21-day cycles and Lugtenburg et al teach successful treatment of DLBLC with subcutaneous epcoritamab in DLBCL in 28 day cycles (q1w: cycle 1-2; q2w cycles 3-6; and q4w thereafter). Additionally, it would have been obvious to routinely optimize the dose after combining the therapies. Furthermore, it would be obvious at the time of effective filing to one of ordinary skill in the art with a reasonable expectation of success that routine optimization after combining therapies that are known in the art to work in DLBLC would result in successfully treating DLBLC because Lignon et al teach successful treatment of DLBLC with intravenous rituximab at 375mg/m2, dexamethasone 40mg/ day, cytarabine 2g/m2, and oxaliplatin 100g/m2 (RDHAX) in DLBLC patients in 21-day cycles and Lugtenburg et al teach successful treatment of DLBLC with subcutaneous epcoritamab in DLBCL in 28 day cycles (q1w: cycle 1-2; q2w cycles 3-6; and q4w thereafter).
Furthermore, Applicant attempts to give a description of unexpected results. However, Lignon et al teach the CR was 64%. The CR of 69% presented by Applicant is not an unexpected result. It is well within the expected range that one of ordinary skill would expect by combining the therapies as discussed in the 35 USC 103 rejection.
Lastly, Applicant's arguments are not found persuasive with respect to unexpected results, because the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must. be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the unexpected properties are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted. In order to demonstrate that the claimed invention yields unexpected results, Applicant is encouraged to provide evidence of such in the form of an affidavit or declaration, or clearly point out such evidence in the specification as originally filed.
Therefore, the 35 USC 103 rejection is maintained.
Regarding the Double Patenting rejection in view of 11083383, Applicant’s arguments and amendments have been fully considered and are persuasive. Specifically, a typographical error was made in the rejection of the patent and is therefore, withdrawn.
Regarding the Double Patenting rejections of US12435154, US11535679, US11845805, US11858995 US 17/923,317, US 18/025,203, US 18/025,208, and US 18/500,799, Applicant’s arguments and amendments have been fully considered and are not persuasive. Specifically Applicant claims the subject matter of the instant application is not disclosed. The Double Patenting rejections in view of the prior art as disclosed in the Double Patenting Rejection render obvious the subject matter of the instant application. Therefore the Double Patenting rejections are maintained.
Regarding the Double Patenting rejections of U.S. Patent No. 11,548,952 and U.S. Application No. 18/855,842, Applicant has asked that these rejections be held in abeyance. Therefore, these double patenting rejections have been held in abeyance and rejections are maintained for reasons of record.
Rejections Maintained- Nonfinal 12/23/2025
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, 52, 53 and 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010) in view of Lugtenburg et al (Lugtenburg et al, blood, 2019, 134, 758; published 11/13/2019).
Lignon et al teach use of intravenous rituximab at 375mg/m2, dexamethasone 40mg/ day, cytarabine 2g/m2, and oxaliplatin 100g/m2 (RDHAX) in DLBCL patients in 21-day cycles (Lignon et al, pg. 263, RDHAX Regimen section). Patients were classified as achieving complete response, partial response, stable disease or progressive disease (Lignon et al, pg. 265, Response to Therapy Section). It is noted that [0103] of the published instant application states that “[a]s used herein, ‘oxaliplatin/carboplatin’ is intended to refer to oxaliplatin or carboplatin.” As such the claims do not require carboplatin.
Therefore Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Lignon et al do not teach a method of treating DLBCL with subcutaneous epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. This deficiency is remedied by Lugtenburg.
Lugtenberg et al teach the use of subcutaneous epcoritamab in DLBCL in 28 day cycles (q1w: cycle 1-2; q2w cycles 3-6; and q4w thereafter) (Lugtenburg et al, pg. 2, Introduction and Methods Sections).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lignon et al with Lugtenburg et al to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. One of ordinary skill in the art would have been motivated to do so, because Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Furthermore, based upon the teachings of Lugtenburg et al, one of ordinary skill in the art would have been motivated to treat DLBCL with epcoritamab. As such one of ordinary skill in the art would have been motivated to modify the invention Lignon et al, which teaches the administration of RHDAX/C in DLBCL patients is effective in treating DLBCL to further include epcoritamab, because there would have been a reasonable expectation that the resultant invention, which comprises a method of treating DLBLC with epcoritamab and RDHAX/C is effective in treating DLBCL patients.
Regarding claims 4, 7-10, 39-40, and 69-70, Lignon et al teach that the DLBCL patients are eligible for and treated with ASCT (Lignon et al, pg. 268, column 2, paragraph 1).
Regarding claims 1-3, 5-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, and 68-70, the doses and administration schedules represent obvious variants that are a result of routine optimization.
With respect to the epcoritamab and RDHAX/C doses and administration schedules, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation, which states that:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug doses or administration schedules, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed epcoritamab and RDHAX/C doses and administration schedules are akin to the variables discussed in the cited MPEP passage, because epcoritamab and RDHAX/C doses and administration schedules are an optimizable variable that would affect at least at least efficacy and safety. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed epcoritamab and RDHAX/C doses and administration schedules, because such optimization would produce a more effective/safer invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to epcoritamab and RDHAX/C doses and administration schedules, and these variables achieve a recognized result, such as drug efficacy and/or drug toxicity. Accordingly the recited epcoritamab and RDHAX/C doses and administration schedules are result-effective variables that achieve a recognized result, such as drug efficacy and/or drug toxicity, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the recited doses and administration schedules were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
The courts have also found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Therefore, the claimed epcoritamab and RDHAX/C doses and administration schedules represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claims 52 and 53, Lignon et al teach some DLBCL patients have relapsed and/ or were refractory to other treatments (Lignon et al, pg. 264, Table 2).
Claim(s) 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010) in view of Lugtenburg et al (Lugtenburg et al, blood, 2019, 134, 758; published 11/13/2019), and Caimi et al (Caimi et al, blood, 2018, 132, 397; published 11/29/2018).
Lignon et al teach use of intravenous rituximab at 375mg/m2, dexamethasone 40mg/ day, cytarabine 2g/m2, and oxaliplatin 100g/m2 (RDHAX) in DLBCL patients in 21-day cycles (Lignon et al, pg. 263, RDHAX Regimen section). Patients were classified as achieving complete response, partial response, stable disease or progressive disease (Lignon et al, pg. 265, Response to Therapy Section). It is noted that [0103] of the published instant application states that “[a]s used herein, ‘oxaliplatin/carboplatin’ is intended to refer to oxaliplatin or carboplatin.”
Therefore Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Lignon et al do not teach a method of treating DLBCL with subcutaneous epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. This deficiency is remedied by Lugtenburg.
Lugtenberg et al teach the use of subcutaneous epcoritamab in DLBCL in 28 day cycles (q1w: cycle 1-2; q2w cycles 3-6; and q4w thereafter) (Lugtenburg et al, pg. 2, Introduction and Methods Sections). Lignon and Lugtenberg et al do not teach a combination for treating DLBCL with epcoritamab and RDHAX/C wherein carboplatin is administered once every three weeks for three 21 day cycles. This deficiency is remedied by Caimi et al.
Caimi et al teaches RICE (which includes carboplatin) is used to treat DLBCL in 21 day cycles for three cycles (Caimi et al, Methods Section).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lignon et al with Lugtenburg et al and Caimi et al to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. One of ordinary skill in the art would have been motivated to do so, because Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Additionally, Caimi et al teach a method of treating DLBCL with RICE over three 21-day cycles. Furthermore, based upon the teachings of Lugtenburg et al, one of ordinary skill in the art would have been motivated to treat DLBCL with epcoritamab. As such one of ordinary skill in the art would have been motivated to modify the invention Lignon et al, which teaches the administration of RHDAX/C in DLBCL patients is effective in treating DLBCL to further include epcoritamab and carboplatin, because there would have been a reasonable expectation that the resultant invention, which comprises a method of treating DLBLC with epcoritamab and RDHAX/C is effective in treating DLBCL patients. The invention of Lignon et al, Lugtenburg et al, and Caimi et al meets the limitations of claims 31 and 32.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of effective filing.
Claim(s) 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010) and Lugtenburg et al (Lugtenburg et al, blood, 2019, 134, 758; published 11/13/2019), as applied to claims 1-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, 52, 53 and 68-70, and further in view of Aukema et al (Blood, 2011, 117, 8; published 02/24/2011).
As indicated above one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lignon et al with Lugtenburg et al to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. These references do not teach or suggest double-hit DLBCL or DLBCL that is follicular lymphoma grade 3B. These deficiencies are remedied by Aukema et al.
Aukema et al teach double-hit DLBCL, see Table 1, and at p. 2325, second full column, Aukema et al. teach that some double-hit lymphomas are follicular lymphoma grade 3B.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lignon et al and Lugtenburg et al with those of Aukema et al. to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. One of ordinary skill in the art would have been motivated to do so, because Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease, wherein said DLBCL is double-hit and/or follicular lymphoma grade 3B. One of ordinary skill in the art would have been motivated to do so, because Lignon et al and Lugtenburg et al teach or suggest a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Furthermore Aukema et al teach double-hit DLBCL, see Table 1, and at p. 2325, second full column, Aukema et al. teach that some double-hit lymphomas are follicular lymphoma grade 3B. One of ordinary skill in the art would have been motivated to administer the method of Lignon et al and Lugtenburg et al to double-hit and/or follicular lymphoma grade 3B DLBCL patients, because there would have been a reasonable expectation that the method of Lignon et al and Lugtenburg et al would provide a therapeutic benefit to double-hit and/or follicular lymphoma grade 3B DLBCL patients.
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 1-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, 52, 53 and 68-70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,435,154 in view of Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010).
Claims 1-3 of the conflicting patent recite a method of treating DLBCL by administering subcutaneous epcoritamab to a subject in need thereof.
Lignon et al teach use of intravenous rituximab at 375mg/m2, dexamethasone 40mg/ day, cytarabine 2g/m2, and oxaliplatin 100g/m2 (RDHAX) in DLBCL patients in 21-day cycles (Lignon et al, pg. 263, RDHAX Regimen section). Patients were classified as achieving complete response, partial response, stable disease or progressive disease (Lignon et al, pg. 265, Response to Therapy Section).
Based upon the teachings of Lignon et al., one of ordinary skill in the art would have been motivated to modify the conflicting claims to recite the administration of rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin. One of ordinary skill in the art would have been motivated to do so, because there would have been a reasonable expectation that the resultant invention is effective in treating DLBCL.
Regarding claims 4, 7-10, 39-40, and 69-70, Lignon et al teach that the DLBCL patients are eligible for and treated with ASCT (Lignon et al, pg. 268, column 2, paragraph 1).
Regarding claims 1-3, 5-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, and 68-70, the doses and administration schedules represent obvious variants that are a result of routine optimization.
With respect to the epcoritamab and RDHAX/C doses and administration schedules, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation, which states that:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug doses or administration schedules, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed epcoritamab and RDHAX/C doses and administration schedules are akin to the variables discussed in the cited MPEP passage, because epcoritamab and RDHAX/C doses and administration schedules are an optimizable variable that would affect at least at least efficacy and safety. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed epcoritamab and RDHAX/C doses and administration schedules, because such optimization would produce a more effective/safer invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to epcoritamab and RDHAX/C doses and administration schedules, and these variables achieve a recognized result, such as drug efficacy and/or drug toxicity. Accordingly the recited epcoritamab and RDHAX/C doses and administration schedules are result-effective variables that achieve a recognized result, such as drug efficacy and/or drug toxicity, and it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the recited doses and administration schedules were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
The courts have also found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Therefore, the claimed epcoritamab and RDHAX/C doses and administration schedules represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claims 52 and 53, Lignon et al teach some DLBCL patients have relapsed and/ or were refractory to other treatments (Lignon et al, pg. 264, Table 2).
Claims 31 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,435,154 in view of Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010), as applied to claims 1-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, 52, 53 and 68-70, and further in view of Caimi et al (Caimi et al, blood, 2018, 132, 397; published 11/29/2018).
Based upon the teachings of Lignon et al., one of ordinary skill in the art would have been motivated to modify the conflicting claims to recite the administration of rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin.
Caimi et al teaches RICE (which includes carboplatin) is used to treat DLBCL in 21 day cycles for three cycles (Caimi et al, Methods Section).
Based upon the teachings of Caimi et al, one of ordinary skill in the art would have been motivated to combine the teachings of Lignon et al, the conflicting claims, and Caimi et al to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. One of ordinary skill in the art would have been motivated to do so, because Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Additionally, Caimi et al teach a method of treating DLBCL with RICE over three 21-day cycles. Furthermore, based upon the teachings of the conflicting claims, one of ordinary skill in the art would have been motivated to treat DLBCL with epcoritamab. As such one of ordinary skill in the art would have been motivated to modify the invention Lignon et al, which teaches the administration of RHDAX/C in DLBCL patients is effective in treating DLBCL to further include epcoritamab and carboplatin, because there would have been a reasonable expectation that the resultant invention, which comprises a method of treating DLBLC with epcoritamab and RDHAX/C is effective in treating DLBCL patients.
Claims 50 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,435,154 in view of Lignon et al (Lignon et al, clinical lymphoma myeloma and leukemia, vol 10, no 4, 282-269, 2010; published 08/2010), as applied to claims 1-18, 20-21, 23-24, 26-29, 34-35, 37-40, 47-49, 52, 53 and 68-70, and further in view of Aukema et al (Blood, 2011, 117, 8; published 02/24/2011).
Based upon the teachings of Lignon et al., one of ordinary skill in the art would have been motivated to modify the conflicting claims to recite the administration of rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin.
Aukema et al teach double-hit DLBCL, see Table 1, and at p. 2325, second full column, Aukema et al. teach that some double-hit lymphomas are follicular lymphoma grade 3B.
Based upon the teachings of Aukema et al., one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lignon et al and the conflicting claims with those of Aukema et al. to arrive at a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. One of ordinary skill in the art would have been motivated to do so, because Lignon et al teach a method of treating DLBCL with RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease, wherein said DLBCL is double-hit and/or follicular lymphoma grade 3B. One of ordinary skill in the art would have been motivated to do so, because Lignon et al and the conflicting claims teach or suggest a method of treating DLBCL with epcoritamab and RDHAX/C administered in 21-day cycles until complete response, partial response, stable disease or progressive disease. Furthermore Aukema et al teach double-hit DLBCL, see Table 1, and at p. 2325, second full column, Aukema et al. teach that some double-hit lymphomas are follicular lymphoma grade 3B. One of ordinary skill in the art would have been motivated to administer the method of Lignon et al and the conflicting claims to double-hit and/or follicular lymphoma grade 3B DLBCL patients, because there would have been a reasonable expectation that the method of Lignon et al and the conflicting claims would provide a therapeutic benefit to double-hit and/or follicular lymphoma grade 3B DLBCL patients.
Claims 1-18, 20-21, 23-24, 26-29, 31-32, 34-35, 37-40, 47-53 and 68-70 are rejected under non-statutory double patenting over the reference patents listed in the following table:
Patent Number
Brief Description of the Invention
Pertinent Claims
12435154
Method of Treating a subject with DLBCL by administering epcoritamab
69-97
11535679
Method of Treating a subject with DLBCL by administering epcoritamab
49-54, 57-60, 62-78
11845805
Method of Treating a subject with DLBCL by administering epcoritamab
66-71, 73, 75, 77-101
11858995
Method of Treating a subject with DLBCL by administering epcoritamab
43-52, 55-59, 61-75
11083383
Method of Treating a subject with DLBCL by administering epcoritamab
50, 58, 65-67, 69-93
11548952
Method of Treating a subject with DLBCL by administering epcoritamab
69-73, 76-82, 84-98
It is further noted that some of the above-mentioned reference patents are not drawn to methods of treating DLBCL with epcoritamab and RDHAX/C but rather to (i) epcoritamab alone, (ii) epcoritamab and other therapies. However, each category of invention specified above comprises/recites the same/similar active steps for treating a subject with DLBCL. Even if the method of treating DLBCL is not identical to the instant application, the inventions are analogous to Lugtenburg et al, who teaches the instant method of treating a subject with DLBCL. Thus, the above-mentioned reference patents, in view of Lignon et al, would render any method of treating DLBCL with epcoritamab obvious. The additional limitations of the instant claims would further be rendered obvious under the same art references utilized above.
In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant and each of the copending sets of claims are obvious as they read on treating DLBCL with epcoritamab obtained by the same method as instantly claimed.
Similarly, claims 1-18, 20-21, 23-24, 26-29, 31-32, 34-35, 37-40, 47-53 and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the copending Application Numbers listed in the following table:
Application Number
Brief Description of the Invention
Pertinent Claims
17923317
Method of Treating a subject with DLBCL by administering epcoritamab
69-70, 72-89, 98-108
18025203
Method of Treating a subject with DLBCL by administering epcoritamab
1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, 64-67
18025208
Method of Treating a subject with DLBCL by administering epcoritamab
1-3, 7, 9, 12, 15, 17, 20, 22, 24-25, 29-36, 50-51
18500799
Method of Treating a subject with DLBCL by administering epcoritamab
1-8, 12, 15, 17, 20, 23, 26, 29, 33-38, 46-50, 64-67
18855842
Method of Treating a subject with DLBCL by administering epcoritamab
1, 5, 9, 11-12, 20-21, 29, 33, 39, 44, 46, 48-49, 60-63, 72-73, 83, 86-87, 97-101
It is further noted that some of the above-mentioned reference patents are not drawn to methods of treating DLBCL with epcoritamab and RDHAX/C but rather to (i) epcoritamab alone, (ii) epcoritamab and other therapies. However, each category of invention specified above comprises/recites the same/similar active steps for treating a subject with DLBCL. Even if the method of treating DLBCL is not identical to the instant application, the inventions are analogous to Lugtenburg et al, who teaches the instant method of treating a subject with DLBCL. Thus, the above-mentioned reference patents, in view of Lignon et al, would render any method of treating DLBCL with epcoritamab obvious. The additional limitations of the instant claims would further be rendered obvious under the same art references utilized above.
In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant and each of the copending sets of claims are obvious as they read on treating DLBCL with epcoritamab obtained by the same method as instantly claimed.
Conclusion
THIS ACTION IS MADE FINAL. 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.
No claim is allowed.
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/J.K.D./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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