DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 05/13/2020, claims foreign priority to application EP20305223.8
filed 03/03/2020, and domestic benefit to US provisional applications 62/899,088, filed 09/11/2019; 62/860,739, filed 06/12/2019; and 62/847,825, filed 05/14/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 10/28/2025 is acknowledged. Claim 21 is amended and claims 1, 3-16, 19-20, 22-47, 49-50, 54-70, and 73-84 are cancelled. Claims 2, 17-18, 21, 48, 51-53, 71-72, and 85-95 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/28/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 04/29/2025, claim 21 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to change the dependency from claim 18 to 17 has overcome the rejection and the rejection is withdrawn.
The following grounds rejections are maintained.
Claim Interpretation
Claims 48 and 51-52 are drawn to the method of claim 2 and recite limitations drawn to the duration of the infused doses. The limitation “infused over a duration of” is interpreted as being drawn to the duration of infusion from start to finish including any interruption time that may occur. This interpretation is supported by the instant specification [0163], table 9, which states that “Duration of infusion was defined from the start time of infusion to the end time of infusion, including interruption time (if any).”
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 18, 53, 71-72, and 86-95 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Martin, T., et al (2017) A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma Blood 129(25); 3294-3303, King, T., et al (2018) Best practice for administration of daratumumab in multiple myeloma: Austrailian myeloma nurse expert opinion Asia Pac J. Oncol Nurs 5; 270-284, Hong, D.I., et al (2012) Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies Expert Rev. Clin. Immunol. 8(1); 43-54, Nooka, A.K., et al (2018) Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab Journal of Oncology Practice 14(7); 414-423, and Barr, H., et al (2018) Ninety-Minute Dartumumab infusion is safe in multiple myeloma Leukemia 32 (11); 2495-2518.
Martin discusses the results from a phase 1b, open-label, dose-escalation study assessing the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab in patients with relapsed/refractory multiple myeloma. In the study, isatuximab was administered by IV infusion at dosages of 3, 5, or 10 mg/kg every other week (Q2W) or 10 or 20 mg/kg weekly (QW) for 4 weeks and then Q2W thereafter (QW/Q2W) (abstract; page 3295, study design). Martin further discloses that the administration was in combination with lenalidomide (len) and dexamethasone (dex) in continuous 28-day cycles (paragraph bridging columns, page 3295). In the study, patients received a median of 9 cycles (range 1-37) with 21 patients receiving at least 12 cycles (page 3297, left column, paragraph 2), indicating greater than 5 dosages of isatuximab. For instance, the QW/Q2W administration with a 28-day cycle for 12 cycles would indicate approximately 26 dosages ((4x1)+(2x11)).
Martin teaches that, to mitigate infusion associated reactions (IARs), the protocol mandated use of standard premedications, including dexamethasone 40 mg IV or methylprednisolone 100 mg IV; diphenhydramine 50 mg IV or equivalent; ranitidine 50 mg IV or equivalent; and acetaminophen 650-1000 mg oral administration, up to 60 minutes before each infusion. Dex was part of the combination regimen, so it was used as both the premedication and backbone therapy (page 3295, right column, paragraph 3).
Infusion associated reactions (IARs) occurred only with the first infusion in 28 of the 32 patients, and no IARs were recorded after the fourth infusion. IARs were predominantly grade 1/2 in severity; 5 patients had grade 3 IARs, and no patients had grade 4 IARs. The 5 patients who had grade 3 AIRs discontinued treatment. All IARs leading to discontinuation occurred within the first infusion except for the case of maculopapular rash, which occurred with the third infusion. The starting infusion rate was 250 mg/h in 3 of the patients who discontinued treatment due to IARs. In the cohorts examined in the dose expansion part of the study, IARs were more common at the 250 mg/h initial isatuximab infusion rate compared with the 175 mg/h initial infusion rate prompting use of the lower infusion rate across the isatuximab program (page 3297, right column, paragraph 2). Figure 1, page 3298, provides the IARs by grade and infusion number for the study according to dosage and infusion rate. The figure demonstrates a significant decrease in the % of patients experiencing IARs from the first infusion to the infusions >1. The figure description further discloses that no IARs were observed after the fourth infusion (page 3298). Martin teaches adverse events including fatigue, nausea, pyrexia, cough, and diarrhea (page 3297, Table 2)
Martin teaches that the characteristics of the IARs observed in the study were consistent with the notion that infusion and hypersensitivity reactions to mAbs tend to occur during the first or second infusions, as has been observed in studies of isatuximab monotherapy as well as studies of daratumumab. The incidence and severity of IARs appeared greater with the 250 mg/h vs 175 mg/h initial infusion rate. These data were taken to support the use of this slower initial infusion rate in future studies (page 3300, left column, paragraph 1).
Martin further teaches that the median infusion duration for the first infusion was 3.7 and 3.1 hours (range 2-7 hours) for the isatuximab 10 mg/kg Q2W and QW/Q2W cohorts, respectively, and 4.9 (range 0-11 hours) for the 20 mg/kg. Median duration for subsequent infusions was slightly shorter for both doses: 2.3-2.4 (0-4) and 4.6 (1-26) hours at 10 and 20 mg/kg, respectively (paragraph bridging pages 3297-3298).
Martin teaches that therapies for multiple myeloma include proteasome inhibitors, such as bortezomib, carfilzomib, and ixoazomib, immunomodulatory drugs, such as thalidomide, lenalidomide, and pomalidomide, and histone deacetylase inhibitors, such as panbinostat and vorinostat, and that these therapies have been used in various combinations resulting in improved response rates and longer progression free survival compared with traditional therapies (page 3294, left column, paragraph 1).
Martin, however, does not disclose the infusion regimen of the instant claims, that the infusion volume is 250 mL, or that the premedication is not administered prior to the fifth (claim 2), fourth (claim 94), or third (claim 95) dose.
King teaches that patients with multiple myeloma (MM) are typically of an advanced age and have significant co-existing medical conditions. King further teaches that these patients have often had multiple lines of therapy and as such experience disease-related effects alongside associated treatment toxicities. King highlights key nursing care considerations and practical management aspects to improve the treatment experience of patients receiving daratumumab infusions (abstract).
King teaches that novel agents such as daratumumab have been recently approved for use in the relapsed/refractory (RR) setting and that daratumumab is a human IgGк monoclonal antibody that targets CD38, which is highly expressed on myeloma cells. King teaches that daratumumab has direct and indirect antitumor activity and diverse mechanisms of action. In heavily pretreated patients with relapsed or RR MM, single-agent daratumumab was associated with an overall response rate of 31% and a medial OS of 20.1 months (page 271, paragraph bridging columns). King further teaches that clinical trials evaluating the combination of daratumumab with proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) for the treatment of relapsed or RR MM, adding daratumumab improved PFS while maintaining an acceptable safety profile. King teaches the combination of daratumumab with bortezomib and dexamethasone (page 271, right column, paragraph 2) as well as daratumumab plus lenalidomide and dexamethasone (page 272, left column, paragraph 2). King further teaches that, in Australia, daratumumab is approved for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of patients with MM who have received at least one prior line of therapy (page 272, left column, paragraph 3).
King further teaches that clinical studies have found that daratumumab showed good tolerability as a monotherapy and in combination with standard therapies. However, the administration does require specific management considerations. King teaches that daratumumab is administered intravenously and infusion-related reactions (IRRs), common to all monoclonal antibodies, may occur (page 272, left column, paragraph 4). King further teaches that IRRs were reported in approximately half of all patients treated with daratumumab, with most occurring during the first infusion and that the occurrence of IRRs can be influenced by infusion rate. King further teaches that in clinical trials of both monotherapy and combination treatments, 46% of patients experienced IRRs with the first infusion, 2% with the second infusion, and 3% with subsequent infusions. King teaches that IRRs were generally mild and discontinuations were rare (page 272, right column, paragraph 2). King teaches that daratumumab IRRs are generally characterized by nasal congestion, throat irritation, cough, chills, vomiting, nausea, dyspnea, and allergic rhinitis (paragraph bridging pages 272 and 273; Table 3 footnote). King also teaches adverse reactions including upper respiratory tract infections and pyrexia (Table 3).
King teaches that special care needs to be taken for patients with chronic obstructive pulmonary disease (COPD) or chronic asthma and that, for patients with a history of COPD or severe persistent asthma, post-infusion medications such as antihistamines, short- and long-acting bronchodilators, and inhaled corticosteroids should be considered (page 274, left column, paragraph 4).
King teaches that daratumumab monotherapy is administered weekly during the first 8 weeks, every 2 weeks for the following 16 weeks, and monthly thereafter (page 275, right column, paragraph 2). King further teaches the administration of 16 mg/kg of daratumumab (page 275, Figure 2). King provides the daratumumab administration guidelines in Table 4, which provides infusion rates for daratumumab administration (page 278). Table 4 from King is duplicated below:
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573
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As shown above, King teaches an administration regimen for daratumumab which comprises an infusion rate escalation regimen in which the flow rate is increased every 60 minutes. The administration regimen demonstrates increased antibody administration from the first to second and second to third administrations either through the drug concentration (based on total infusion volume), or the infusion rate.
Hong teaches that monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion related reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Hong teaches that patients who experience acute infusion related reactions face the prospect of stopping treatment or switching to alternative, and potentially more toxic or inferior treatments. Hong suggests that another option that overcomes the treatment hurdle of these reactions is rapid desensitization. A procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. Hong teaches that, while the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who would otherwise not be able to tolerate monoclonal antibody therapy due to anaphylaxis. Hong provides a review of the current literature at the time of publication on desensitization and re-administration protocols (abstract).
Hong teaches that desensitization protocols were first conceived in the 1940s and have since been successfully performed with a variety of medications (page 44, left column, paragraph 2). Hong further teaches that some reactions to mAbs occur on first exposure and skin test data is generally not helpful. While desensitization protocols vary from group to group, all start by giving the patient an extremely small dose, often 102-103-fold lower than the full dose, and gradually increasing the infusion rate in a step-wise fashion over fixed time intervals until the patient is ‘tolerized’ to the offending agent. Hong teaches that the stepwise nature of desensitization protocols makes it unlikely that the patient will suffer a reaction as severe in magnitude as the initial reaction since the drug is typically infused in a slow, highly controlled fashion, and there are multiple built-in breakpoints for medical intervention if needed (page 44, right column, paragraph 2).
Hong teaches desensitization protocols including those for four antibodies including rituximab, infliximab, cetuximab, and trastuzumab (abstract). Hong teaches 250 mL standard volume bags, and protocols in which infusion rates are increased every 15 minutes (table 1, page 46; table 2, page 47; table 5, page 50) as well as every 30 minutes (table 3, page 48; table 4, page 49). Hong teaches infusion rates ranging from 2.0 mL/hr to 80 mL/hr (table 1, page 46; table 2, page 47; table 4, page 49; table 5, page 50).
Hong further teaches a study in which no premedications were given and the TNF-α inhibitor antibody adalimumab was administered over six injections spaced 60 minutes apart with each injection roughly doubling the dosage of the prior step (page 48, right column, paragraph 1). Hong teaches that some groups have suggested that slowing the infusion rate can be helpful in some instances of acute infusion reactions. Several groups have also developed protocols for administration with routine premedication with steroids, antihistamines, and acetaminophen. However, at least two open studies on adverse drug reactions to infliximab suggest that there is no advantage of a routine premedication for patients who do not have a prior history of infusion reactions (page 46, right column, paragraph 3).
Hong concludes that in the 5 years following publication, the expansion and universal application of desensitization protocols would occur allowing for all patients with acute hypersensitivity reactions to be treated with first-line therapy mAbs to cure or modify diseases such as cancer (paragraph bridging left and right column, page 51).
Nooka studied antimyeloma monoclonal antibodies elotuzumab, a signaling lymphocytic activation molecule F7 monoclonal antibody, and daratumumab, a CD38 monoclonal antibody, and infusion-related reactions related to their use. Nooka provides practical mitigation strategies to reduce the incidence of these adverse events (abstract).
Nooka teaches that the most common adverse events (AEs) seen with the monoclonal antibodies in myeloma are the infusion-related reactions, mostly grade 1 and 2, commonly seen during the first and second infusions (page 414, right column, paragraph 1). Nooka teaches that infusion-related reactions observed with elotuzumab included fatigue, pyrexia, cough, headache, nausea, and back pain (page 416, left column, paragraph 4). Infusion related reactions to daratumumab are taught to included fatigue, nausea, anemia, back pain, cough, upper respiratory tract infection, thrombocytopenia, and neutropenia (page 417, right column, paragraph 3). Nooka teaches that in daratumumab treated patients, infusion-related reactions were reported in 48% of patients and most infusion-related reactions, 96%, occurred during the first infusion and the incidence decreased during second infusions to 7%. Nooka also teaches that infusion-related reactions were safely managed with pre- and post-infusion medications which consisted of antihistamines, corticosteroids, and acetaminophen (page 417, right column, paragraph 3).
Nooka teaches that given the higher rates of daratumumab infusion related reactions with the first infusion and lower rates with subsequent infusions, it is recommended that the first and subsequent administrations be administered differently. Nooka goes on to teach infusion rate escalation regimens that can be used to reduce infusion related reactions to the antibodies (page 419, left column, paragraph 1; page 418, Table 2).
Nooka teaches escalation regimens comprising administration of a total volume ranging from 250 mL to 1,000 mL, with rates ranging from 30 mL/hr to 300 mL/hr (page 418, table 2).
Nooka further teaches that patients with a higher risk of respiratory complications, such as those with chronic obstructive pulmonary disease, asthma, and forced expiratory volume in 1 second <80%, were treated with post infusion medication (paragraph bridging pages 419 and 420).
Nooka teaches combination therapies including daratumumab in combination with bortezomib and dexamethasone and in combination with lenalidomide and dexamethasone (page 418, left column, paragraph 1; page 417, right column, paragraph 3).
Barr teaches that daratumumab is a first-in-class anti-CD38 monoclonal antibody approved for relapsed and refractory MM. CD38 is expressed on airway smooth muscle cells and infusion related reactions were marked by symptoms including cough, wheezing, and rhinorrhea, similar to those of allergic rhinitis. In two pivotal studies, most IRRs, specifically 95.8%, occurred during the first infusion with a decrease incidence of IRRs during second and subsequent infusions, down to 7%. No relationship between daratumumab serum levels and development of IRRs was observed (page 1, paragraph 1). The incidence and severity of IRRs has led to the recommended administration rates which result in infusion times for the first, second, and subsequent infusions of 6.5, 4.5, and 3.5 hours respectively (page 1, paragraph 2).
Due to the low incidence of infusion related reactions after the first infusion, it was hypothesized that increasing the infusion rate of the third and subsequent doses of daratumumab would not affect the safety profile. Previously, this concept was studied with rituximab in which the second or subsequent infusions were given at a rapid 1 hour infusion rate (page 2, paragraph 2). Barr reports a 90 minute estimated infusion time for a total volume of 550 mL. The infusion rate was calculated to deliver 20% of the dose in over 30 minutes at 200 mL/hr, and then the rate was increased further to deliver the remaining 80% over 60 minutes at 450 mL/hr.
The 90 minute infusion was well tolerated in multiple myeloma patients receiving their third dose or beyond and saved patients 2 hours of infusion time per dose. The most common premedication combination was acetaminophen, diphenhydramine, famotidine, and dexamethasone. Since implementing the accelerated infusion as a new standard-of-care at the institution, Barr teaches that the premedication strategy for the first dose involves most standard medications which were then pruned to dexamethasone and montelukast po with the third dose (first accelerated dose) and then dexamethasone IV only thereafter (page 3, paragraph 2).
Barr teaches that the disclosed strategies decrease time in the infusion center, reduce healthcare resources utilized, and increase efficiency (page 3, paragraph 6).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the administration of isatuximab in the method of Martin to use a desensitization protocol, such as that taught by Hong. It would have further been obvious to optimize the protocol using the infusion flow rates, volumes, and step times known in the art as disclosed by Hong and Nooka. It would have further been obvious to administer premedication to treat infusion related reactions prior to at least the first and second dose of isatuximab then tapering the premedication based on infusion number, which could begin on the third, fourth, or fifth dose as suggested by Barr and supported by Martin and Hong and would reasonably be determined by a practitioner on a patient-by-patient basis.
An ordinarily skilled artisan would have been motivated to use the regimen of King for the administration of isatuximab to reduce infusion related reactions that are routine with the administration of mAbs by desensitizing the patient as disclosed by King, Hong, and Nooka. An ordinarily skilled artisan would have had a reasonable expectation of success as both Martin and King are teaching the administration of anti-CD38 antibodies for the treatment of multiple myeloma. Additionally, Martin and King teach overlapping infusion related reactions for isatuximab and daratumumab including fatigue, nausea, pyrexia, coughing, and diarrhea, reactions which Hong teaches can be reduced using desensitization methods.
With regards to the regimen specifically recited in the claims, the prior art demonstrates that the infusion rate, total volume (which would impact the concentration of the antibody during infusion), and the steps between increases were all viewed as result-effective variables. The applied references also demonstrate that the prior art was aware that the initial infusions are most important for using step-wise infusion rates as they carry the heaviest risk of infusion related reactions and that, over time, patients will become desensitized to the monoclonal antibody infusions allowing for higher infusion rates with less reaction. The determination of exact infusion regimens for a specific monoclonal antibody in an effort to reduce infusion-related reactions is considered to be routine optimization when general regimens were known as well as considerations to be made during regimen selection and implementation.
MPEP 2144.05 (II) states "’[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)” and "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)”.
In this case, as discussed in detail above, King teaches an infusion regimen for an anti-CD38 antibody for the treatment of multiple myeloma in which the infused amount of antibody increases over three infusions with infusion rates of 50 mL/hr to 200 mL/hr. Hong teaches that antibody infusion rates as low as 2.0 mL/hr had also been used in the prior art for antibody infusion. It would have been obvious to an ordinarily skilled artisan to have used the regimen of King as a starting point for routine optimization to determine the optimal infusion rates for use in the administration of isatuximab and to have used flow rates between 2.0 mL/hr and 200 mL/hr in determining the optimal regimen. One of ordinary skill in the art would have been motivated to optimize the infusion rate as Hong teaches that desensitization protocols may vary slightly from group to group, but all include gradually increasing the rate of infusion in a step-wise fashion until the patient is tolerized to the offending agent. Hong further teaches that the step-wise nature of desensitization protocols makes them unlikely the patient will suffer a reaction as severe in magnitude as the initial reaction since the drug is typically infused in a slow, highly controlled fashion (page 44, right column, paragraph 2).
In the regimen disclosed by King, total infusion volumes of 500 mL and 1000 mL are used. Hong and Nooka demonstrate that total infusion volumes of 250 mL had also been used in antibody desensitization regimens. It would have been obvious to one of ordinary skill in the art to have used the teachings of King as a starting point for routine optimization to determine the optimal total volume for infusion and to have used total volumes of 250 mL, 500 mL, or 1000 mL in determining the optimal regimen. An ordinarily skilled artisan would have been motivated to optimize the total volume infused as the total volume infused would change the concentration of the drug being administered and Hong teaches that studies have included changing the concentration of drug being administered (page 45, left column, paragraph 3). This is also demonstrated by King who changes infusion volume in the regimen, which would change the concentration of the antibody.
In the regimen disclosed by King, infusion rates are increased every 60 minutes. Hong teaches that infusion rate increases every 15 or 30 minutes had also been used in antibody administration regimens. It would have been obvious to an ordinarily skilled artisan to have used the regimen of King as a starting point for routine optimization to determine the optimal time intervals for use in the administration of isatuximab and to have used time intervals of 15 min, 30 min, or 60 min in determining the optimal regimen. One of ordinary skill in the art would have been motivated to optimize the time intervals as Hong teaches that desensitization protocols may vary slightly from group to group, but all include gradually increasing the rate of infusion in a step-wise fashion over fixed time intervals until the patient is tolerized to the offending agent (page 44, right column, paragraph 2).
It would have been obvious to administer premedication to treat infusion related reactions prior to at least the first and second dose of isatuximab then tapering the premedication as the patient experiences reduced infusion related reactions and based on the determinations made by the administering practitioner. The teachings of Barr demonstrate that reducing premedication based on dose number was practiced in the prior art. For instance, as discussed in detail above, Barr teaches that in daratumumab infusion, most standard medications were given for the first dose including acetaminophen (analgesic), diphenhydramine (antihistamine), dexamethasone, and famotidine (H2 antagonist). With the third dose, only dexamethasone and montelukast (bronchodilator/anti-inflammatory) were given and thereafter only dexamethasone (page 3, paragraph 2) indicating that all pre-medications in Barr were stopped, with the exception of the steroid dexamethasone, at the fourth infusion. Hong teaches that several groups have developed protocols for infliximab administration with routine premedication, but that at least two open studies have suggested that there is no advantage of a routine premedication for patients who do not have a prior history of infusion related reactions (page 46, right column, paragraph 3). The teachings of Martin demonstrate significant decreases in IARs between infusion 1 and >1 and teaches that no IARs were observed after the fourth infusion. As such, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to administer premedication at least during the first and second infusion and to taper premedication when the patient does not experience IARs anymore. As Barr demonstrates limited premedication for daratumumab at dose three and no premedication at dose four, and King demonstrates significant reduction in infusion related reactions at doses >1 with no infusion related reactions after the fourth dose, an ordinarily skilled artisan would reasonably expect that the tapering of the premedication could occur around the third or fourth infusion.
Furthermore, it would be obvious for an administering practitioner to make the determination of when premedication is no longer necessary on a case-by-case basis. As the art teaches that infusion related reactions decrease significantly after the first infusion, particularly using a desensitization routine, the determination of optimal premedication administration would be considered to be routine in the art and dependent on patient response. As discussed above in detail, 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. MPEP 2144.05 (II).
Claims 17, 21, 48, and 51-52 are rejected under 35 U.S.C. 103 as being unpatentable over Martin, T., et al (2017) A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma Blood 129(25); 3294-3303, King, T., et al (2018) Best practice for administration of daratumumab in multiple myeloma: Austrailian myeloma nurse expert opinion Asia Pac J. Oncol Nurs 5; 270-284, Hong, D.I., et al (2012) Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies Expert Rev. Clin. Immunol. 8(1); 43-54, Nooka, A.K., et al (2018) Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab Journal of Oncology Practice 14(7); 414-423, and Barr, H., et al (2018) Ninety-Minute Dartumumab infusion is safe in multiple myeloma Leukemia 32 (11); 2495-2518 as applied to claims 2 and 18 above, and further in view of Richardson, P.G., et al (2017) Isatuximab plus pomalidomide/ dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA Phase III study design Future Oncology 14(11); 1035-1047.
The combination of Martin, King, Hong, Nooka, and Barr render obvious the methods of claims 2 and 18 as discussed above.
As discussed above, Martin discloses an administration regimen comprising 10 or 20 mg/kg of isatuximab weekly (QW) for 4 weeks and then Q2W thereafter (QW/Q2W) (abstract), as well as continuous 28-day cycles (paragraph bridging columns, page 3295). For this regimen, Martin teaches infusion durations of 3.1 hours for the first dose and 2.3-2.4 hours for the second dose (paragraph bridging pages 3297-3298).
In the methods of King, the first infusion has a median duration of 7 h, with a median duration of second and subsequent infusions of 4.3 and 3.5 h, respectively (paragraph bridging pages 275 and 276). Barr teaches infusions times of 1 hr and 90 minutes (page 2, paragraphs 2-3).
The combination of the applied references, however, does not explicitly teach that in the QW/Q2W protocol the isatuximab is administered on days 1, 8, 16, and 22 for the QW portion and that subsequent doses are administered on days 1 and 15 for the Q2W portion. Additionally the references don’t explicitly teach the claimed infusion durations.
Richardson teaches that isatuximab (ISA) has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRM (abstract). Richardson describes the design of a phase III study which evaluated ISA in combination with pomalidomide and low-dose dexamethasone (Pom/dex) versus Pom/dex alone in RRM (abstract). Richardson teaches doses of 10 mg/kg of isatuximab given in 28-day cycles, with administration of ISA on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 for subsequent cycles (page 1040, paragraph 3; page 1037, paragraph 2 and paragraph 4; page 1038, paragraph 1).
Richardson further teaches that ISA appears to be unique among anti-CD38 mAbs, in that it is able to induce apoptosis without crosslinking and may be better tolerated with a shorter infusion time (page 1036, Isatuximab, paragraph 1). Richardson teaches that ISA has a shorter infusion time and may represent an advantage for patient convenience compared to daratumumab (pages 1043-1044). Using initial infusion rates of 175 mg/h, Richardson teaches median infusion durations of 3.9 h for the first infusion and 2.8 h for subsequent infusions (page 1038, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention modify the method taught by the combination of Martin, King, Hong, Nooka, and Barr to administer isatuximab on days 1, 8, 15, and 22 of the first cycle, which corresponds with the first four doses, and on days 1 and 15 of each of the one or more subsequent 28-day cycles as taught by Richardson. It would have been obvious to adopt these dosing regimens as Richardson is teaching the design of clinical trials using the dosing regimen for isatuximab. An ordinarily skilled artisan would have had a reasonable expectation of success as Martin and Richardson are teaching the same antibody and, like Martin, Richardson is teaching administration weekly (QW) for four weeks then Q2W thereafter (QW/Q2W) in 28 day cycles.
In regards to claims 48, 51, and 52, as discussed above, King teaches infusion times of 7 h, 4.3 h, and 3.5 h for the first, second, and third infusion, respectively using the protocol described (paragraph bridging pages 275 and 276). In the absence of a definition of “about” in the instant specification, these teachings of King could reasonably be interpreted as meeting the instantly claimed ranges for the first, second, and third dose. That said, as discussed above, Richardson teaches that ISA has a shorter infusion time and may represent an advantage for patient convenience compared to daratumumab (pages 1043-1044). Using initial infusion rates of 175 mg/h, Richardson teaches median infusion durations of 3.9 h for the first infusion and 2.8 h for subsequent infusions. Additionally, based on the combined teachings of the applied references, a skilled artisan would reasonably expect that as the infusion rate increases, the duration of infusion would decrease. As the applied references demonstrate infusion times close to or within the claimed ranges, an ordinarily skilled artisan would reasonably expect the infusion time to be close to or within the claimed ranges. MPEP 2144.05 I. states that “in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Claim 85 is rejected under 35 U.S.C. 103 as being unpatentable over Martin, T., et al (2017) A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma Blood 129(25); 3294-3303, King, T., et al (2018) Best practice for administration of daratumumab in multiple myeloma: Austrailian myeloma nurse expert opinion Asia Pac J. Oncol Nurs 5; 270-284, Hong, D.I., et al (2012) Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies Expert Rev. Clin. Immunol. 8(1); 43-54, Nooka, A.K., et al (2018) Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab Journal of Oncology Practice 14(7); 414-423, and Barr, H., et al (2018) Ninety-Minute Dartumumab infusion is safe in multiple myeloma Leukemia 32 (11); 2495-2518 as applied to claim 2 above, and further in view of Fryar, C.D., et al (2018) Mean body weight, height, waist circumference, and body mass index among adults: United States, 1999-2000 through 2015-2016 National Health Statistics Report 122; 1-16.
The combination of Martin, King, Hong, Nooka, and Barr teach the method of claim 2 as discussed above.
As discussed in above, Martin teaches administration of 10 mg/kg of isatuximab.
The applied references, however, do not disclose the recited the mg of isatuximab.
Fryar studied trends in mean weight in adults in the United States and reports that average weights for men and women in 2016 were 89.9kg and 77.4kg, respectively (abstract; page 5, Table 1). Based on this, the average adult in the US weighed approximately 83.6 kg ((89.9kg+77.4kg)/2) around the effective filing date of the claimed invention.
Using the mean weight taught by Fryar and the weight-based dosages taught by Martin in the methods disclosed by Martin, King, Hong, Nooka, and Barr, the 10 mg/kg dosage of Martin would result in the delivery of approximately 836 mg of isatuximab to the average adult patient (10 mg/kg x 83.6 kg). This dosages falls within with the claimed range of 360 mg – 1600 mg, rendering the claimed range obvious per MPEP § 2144.05. As this is the total dosage of isatuximab that would be administered based on weight based dosage and average patient weight, this dosage in mg would be what is included in the delivery bag.
Response to Arguments
Applicant’s arguments in the response filed 10/28/2025 have been fully considered, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that the rejection reasons that it would have been “obvious to try” the workable ranges recited in the claims. Applicant argues that according to MPEP 2144.05 (II), “obvious to try” rationale for obviousness requires that there be a “finite number” of solutions. Applicant argues that one of skill in the art would have to test a seemingly infinite number of solutions to arrive at the claimed method.
The rejection of record, however, does not rely on an obvious to try rationale (KSR E). Rather, the rejection relies on result effective variables and parameters known in the art and routine optimization, for which MPEP 2144.05 II is cited for support. In the response, applicant cites MPEP 2144.05 IIB for teachings concerning obvious to try.
Specifically, the MPEP states “The Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. 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. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (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, 82 USPQ2d at 1397.””
The rejection relies on the teachings of the prior art in order to establish that antibody administration using incremental escalation regimens were known in the art and used as a means to desensitize patients to antibody infusion. The rejection relies on infusion rates, total infusion volumes, and step times between increases practiced in the art, all of which encompass the parameters of the claimed regimen, and optimization that was routine in the art in order to establish obviousness. The references establish that infusion rate, total volume (which would impact the concentration of the antibody during infusion), and the steps between increases were all viewed as result-effective variables which could be optimized to achieve the lowest infusion related reactions. This is particularly the case as the art demonstrates various infusion rates, total volumes, and steps that have been studied and each of these variables would be expected to change the amount of antibody delivered to the subject over time, thereby allowing for optimization to achieve lower infusion related reactions. Additionally, as discussed in the rejection, the applied references also demonstrate that the prior art was aware that the initial infusion is the most important for using step-wise infusion rates as they carry the heaviest risk of infusion related reactions. The references also disclose that over time, patients become desensitized to the infusions allowing for higher infusion rates with less reaction.
As stated in the rejection, MPEP 2144.05 (II)(A) 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.’”
For reference, MPEP 2144.05 (III) provides arguments that can be used to rebut a prima facie case of obviousness that is based on routine optimization including (A) showing that the claimed range is critical, (B) showing that the prior art teaches away from the claimed invention, (C) showing that the claimed parameters were not recognized as “Result-Effective”, and (D) showing that the claimed parameter is disclosed in a very broad range in the prior art.
Applicant further argues that the claims are directed to a specific infusion method for using isatuximab for the treatment of multiple myeloma and that the inventor discovered the unique combination of dose, dose volume, infusion rate, and premedication regimen to decrease treatment duration while minimizing infusion related adverse events. Applicant argues that this combination is not disclosed in the cited references and is critical to achieving the significant improvements in the application as filed.
To support this argument, applicant references the examples of the instant disclosure in which the claimed infusion regimen was investigated. Applicant argues that the median infusion duration in the fixed volume/fast infusion study decreased from 3.7 for the first infusion to 1.85 for the second infusion and then further decreased to 1.25 hours for subsequent infusions, which are considerably shorter than the 2.9 hours of the slow infusion study. Applicant argues that despite faster infusion rates allowing for decreased infusion duration times, fewer patients experienced infusion reactions in the fixed volume/fast infusion study relative to patients in the parallel slow infusion study (40.4% vs 48.3%) and all reactions in the fixed volume/fast infusion study occurred in the first infusion and were resolved the same day with no reactions greater than grade 3. Applicant references [0270]-[0271] for support. Applicant further argues that the overall response rate between the studies was 60.0 % (fixed volume/fast infusion) vs 60.4% (slow infusion study). Survival rates were also comparable. Applicant argues that, unexpectedly, the 1-year progression free survival rate was higher in the fixed volume/fast study, 55.7%, versus in the slow infusion study, 47.6%, referencing [0317].
Applicant further argues that the fixed volume/fast infusion study shows that the claimed infusion regimen shortens infusion duration time for patients while maintaining efficacy and results in a decreased incidence of infusion related reactions.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
MPEP 716.02(b) III. states that “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)”. MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
In the example discussed by applicant in the response, the claimed regimen, referenced as the “fixed volume/fast infusion study”, is compared to a parallel “slow infusion study”. Based on the specification, the referenced slow infusion study is a study in which isatuximab infusion was administered according to a standard protocol with an infusion rate measured in mg/hr (page 11, [0026]). It appears that the slow infusion study comprised a single infusion rate that was held constant throughout the administration. While the fixed volume/fast infusion study demonstrated better outcomes compared to the parallel study, these results are not unexpected in view of the teachings of the prior art. Specifically, as discussed above, the prior art demonstrates that using escalating infusion regimens desensitizes the subject to the infusion thereby lowering infusion related reactions. Furthermore, the slow infusion study is not considered to be a comparison with the closest prior art, which in this case, would be known infusion rate escalation regimens, such as that disclosed by King for the anti-CD38 antibody daratumumab. As such, it is not demonstrated that the results obtained with the specifically claimed regimen are superior to a degree that they would have been unexpected compared to the regimens of the closest prior art. Additionally, as discussed above regarding routine optimization, these results do not demonstrate that the claimed regimen is critical to achieving the outcomes viewed by applicant as unexpected. This is particularly the case as applicant does not compare to any other escalation regimen in order to establish that the claimed regimen, or any parameter within the claimed regimen, is critical for achieving the results.
The reduction in infusion related reactions demonstrated by applicant when an infusion rate escalation regimen is used would have been expected in view of the teachings of the applied prior art as discussed above. Applicant has not shown that the specific infusion regimen recited in the claims yields unexpected results compared to other escalated infusion regimens. Furthermore, an ordinarily skilled artisan would have expected reduced total infusion times based on the teachings of King who teaches infusion time reductions from the first to second and second to third infusions; as well as the teachings of Richardson who demonstrates that, even with single infusion rates, the infusion time of ISA decreased from 3.9h for the first to 2.8h for the second infusion (page 1038, paragraph 1). Nooka also suggests that lowering the rates of infusion related reactions can facilitate reductions in infusion time (abstract). Furthermore, as discussed above, the comparison offered is to a single infusion rate and does not demonstrate unexpected results compared to the closest prior art which would include any infusion rate escalation regimen of the prior art.
While applicant argues that it would not have been expected that administering isatuximab at a higher infusion rate would result in lower instances of infusion reactions, it is considered that in the context of an escalating infusion rate regimen, this outcome would have been expected. This is particularly the case as the applied references demonstrate that through escalation regimens, patients can be desensitized to the infusion resulting in fewer reactions, particularly in the initial infusions.
As applicant does not provide sufficient evidence to demonstrate that the claimed regimen is critical to achieving the outcomes discussed as being unexpected, specifically through comparison to the closest prior art, the arguments were not found to be persuasive.
Conclusion
No claims are allowed.
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 extension fee 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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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693