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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/27/2026 has been entered.
Claim Status
Claims 50, 53, 56-58, and 62-75 are pending. Claims 51-52, 54-55, and 59-61 were canceled; claims 74-75 were newly added; and claims 50 and 53 was amended in the Reply filed 3/27/2026. Claims 56-58, 64-70, and 72-73 and 75 are withdrawn. Claims 50, 53, 62-63, 71 and 74 are presently considered.
Election/Restrictions
Applicant’s election without traverse of a species of method “wherein a patient, following HCT, is administered 120 mg/kg A1AT twice weekly in addition to prednisone at 2 mg/kg/day, for 28 days, and where the patient received once weekly dosing of A1AT at 120 mg/kg for an additional four weeks” in the Reply filed 5/06/2025 is acknowledged.
Following extensive search and examination, the originally elected species has been deemed obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, the claims have been rejected in view of the originally elected species and claims that do not read upon the originally elected species have been withdrawn.
Claims 56, 58-59, 64-70, and 72-73 remain withdrawn as directed to a non-elected species for reasons of record (see, e.g., Action mailed 6/10/2025 at 3). Newly added claim 75 is withdrawn for the same reason as claims 57-58, of record, as claim 75 is not disclosed within the originally elected species.
Claims 56, 58-59, 64-70, 72-73, and 75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/06/2025.
Per MPEP § 803.02(III)(A), examination has not been extended to non-elected species at this time. However, during search and examination of the elected species art pertinent to non-elected species was discovered. Although examination has not been extended to non-elected species at this time, the incidentally discovered art has been placed on record below as a courtesy to the Applicant and to facilitate compact prosecution.
Claims 50, 53, 62-63, 71, and 74 are presently considered.
Priority
The priority claim to US Provisional Application 62/593,446 (filed 12/1/2017) is acknowledged.
Information Disclosure Statement
Applicant should note that one or more documents disclosed on the IDS form submitted on 3/27/2026 were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest priority claim is to US Provisional Application 62/593,446 (filed 12/1/2017); therefore, all documents published in 2018 or later must be accompanied by both month and date of publication.
References that were not considered have been indicated by strike-though on the attached IDS forms. Although not considered, these documents have been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Interpretation and Examiner Notes
The claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 50 is representative of the pending claim scope:
50. (Previously Presented) A method of treating acute graft versus host disease (aGVHD) in a subject following a hematopoietic cell transplantation (HCT) procedure, wherein the subject has been diagnosed following the HCT procedure with aGVHD, comprising administering a combination of a steroid and alpha-1 antitrypsin (A1AT) according to the following schedule:
administering a steroid to the subject; and
(b) administering a dose of 120 mg/kg A1AT to the subject twice weekly following the aGVHD diagnosis for at least 4 weeks, optionally followed by a dose of 120 mg/kg A1AT once weekly for at least an additional 4 weeks.
Additional claim interpretations are set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Alpha-1 antitrypsin (a.k.a., “A1AT” or “AAT”) is interpreted as described (see, e.g., Spec. filed 11/20/2023 at ¶[032]), and is a naturally occurring mammalian serine protease inhibitor that has been commercially available since the mid 1980’s, and include Prolastin®, Glassia®, Aralast®, Zemaira®, among other trademarks (see, e.g., WO 2017/117558 A11 at ¶[0006]). AAT is naturally present in plasma at ranges of 1.3 to 3.5 mg/ml (see id. at ¶[0005]).
All limitations identified as “optional” (i.e., “optionally followed by…” at instant claims 50-55) does not limit the pending claim scope (see, e.g., MPEP § 2111.04(I)).
“Subject” and “patient” are interpreted as defined (see, e.g., Spec. filed 11/20/2023 at ¶[033]).
“Treatment” is interpreted as defined (see, e.g., Spec. filed 11/20/2023 at ¶[034]).
“Effective amount” and “therapeutically effective amount” are interpreted as described (see, e.g., Spec. filed 11/20/2023 at ¶[036]).
“Hematopoietic cell transplantation” (HCT or HSCT) ” is interpreted as described (see, e.g., Spec. filed 11/20/2023 at ¶¶[037], [043] and [044]-[046]).
“Graft versus host disease” (GvHD) is interpreted as described (see, e.g., Spec. filed 11/20/2023 at ¶¶[038]-[042]).
Examiner notes that AAT was identified as useful in the treatment and prevention of GvHD at least as early as 2006 (see, e.g., US 2009/0118162 A12 at title, abs, claims, passim) and that an artisan would know that AAT may be utilized in the treatment of GvHD, and that such treatment has expected benefits well-known in GvHD arts (see, e.g., id.; see also WO 2017/117558 A13, cited in IDS filed 11/20/2023 as Cite No: 6).
Examiner notes that the amendments to claim 1 as filed 3/27/2026 narrow the scope of the dosage administered from a range (i.e., “at least 90”) to a single, discrete non-variable amount, namely 120 mg/kg.
Claim 74 recites a narrower patient population, “wherein the subject is at risk of developing high risk aGVHD following HCT” (see newly added claim 74), which is not clearly defined on record. Notably, the specification provides a description of “high risk” patients (see, e.g., Spec. filed 11/20/2023 at ¶[053]), but not patients “at risk of developing high risk”. Accordingly, the “at risk of developing high risk…” presumably reads upon all patients following allogeneic HCT (see, e.g., Spec. filed 11/20/2023 at ¶[086]), as they are all at a non-zero chance of being “at risk of developing high risk aGVHD” following treatment (see, e.g., Spec. filed 11/20/2023 at ¶¶[014], [062], [079]). This is reasonable because all patients are treated using the same general approach regardless of being “at risk of developing high risk” (see, e.g., Spec. filed 11/20/2023 at ¶[056], instant claim 50),
Additional claim interpretations are set forth below.
Maintained Claim Rejections4
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 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.
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 50, 53, 62-63, 71 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/117558 A1 (Dinarello et al.; July 6, 2017; cited in IDS filed 11/20/2023 as Cite No: 6).
Claim Interpretation: The applicable claim interpretation has been set forth above and is incorporated herein. Additional claim interpretations are set forth below.
WO’558 pertains to the treatment of subjects having GvHD or acute GvHD, or at risk thereof, (see, e.g., WO’558 at abs, ¶¶[0007]-[0008], [0015], [0040], [0056]), including patients at risk of acute GvHD, which is a “major complication” of allogeneic HCT (see, e.g., WO’558 at ¶[0056]), wherein treatment includes the administration of alpha-1 antitrypsin (AAT) to the patients (see, e.g., WO’558 at title, abs, claims 16-18, 20, ¶¶[0008], [0011], [0075]). Regarding the preamble of instant claims 50, 74, and the treatment of aGVHD following an HCT procedure, and the diagnosis of aGVHD following HCT, WO’558 discloses that the embodiments encompass “identifying the subject having GvHD that is steroid-refractory acute GvHD of grade III or grade IV” (see, e.g., WO’558 at ¶[0011], emphasis added; compare id. with added claim 74), and discloses that acute GvHD is encompassed by references to “GvHD” in the prior art disclosure (see, e.g., WO’558 at ¶[0015]). WO’558 identifies that acute GvHD is a known complication following “HCT or other hematopoietic cell implantation events” (see, e.g., WO’558 at ¶[0056], claims 18, 27-28). Accordingly, an artisan would readily appreciate that the disclosed embodiments of WO’558 was applicable to patients diagnosed with acute GvHD following an HCT procedure (see, e.g., WO’558 at ¶¶[0011], [0015], [0056], claims 18, 27-28). Regarding instant claims 50(a), 62, 71, and the administration of a steroid to a subject in need of treatment of aGvHD, WO’558 teaches and claims methods wherein the methods comprise administering to the subject one or more immunosuppressive, immunomodulatory, or anti-inflammatory agents (see, e.g., WO’558 at claims 16-18, ¶[0018]). Critically, WO’558 identifies that such agents may include prednisolone (see id. at ¶¶[0018], [0044], [0050]), methyl-prednisolone (see id.), and prednisone (see id.). Regarding instant claim 50(a), 62, 63, 71, and administration of prednisone at a daily dose of 0.5-3 mg/kg, WO’558 teaches that the disclosed methods may include administration of agents such as prednisone (see, e.g., WO’558 at claims 16-18, ¶¶[0018], [0044], [0050]), and informs artisans that methylprednisolone and prednisone are routinely given at doses of 0.5-2 mg/kg/day to treat acute GvHD (see, e.g., WO’558 at ¶[0050]). Accordingly, an artisan would readily appreciate that the claimed and described methods encompassed the administration of such compounds at least at 0.5-2 mg/kg/day (see, e.g., WO’558 at claims 16-18, ¶¶[0018], [0044], [0050]). Regarding instant claims 50(b), 53, and the administration of AAT to subjects for 28-56 days (i.e., 4 weeks and optionally 4 more weeks), WO’558 discloses and claims methods of treating GvHD by administering AAT to patients “over a 1 to 60-day administration period” (see, e.g., WO’558 at claims 16-18, ¶¶[0010]-[0011])5. Accordingly, the prior art already taught and directed artisans to treatment plans lasting for the same or overlapping duration as presently claimed. Regarding instant claims 50(b), 53, and the administration of AAT to subjects twice (or once) weekly at 120 mg/kg AAT, WO’558 discloses that AAT may be adjusted “according to the individual need” as “determined by a health professional” (see, e.g., WO’558 at ¶[0075]). WO’558 explains that dosage and frequency may range from “about 1.0 mg/kg to about 150 mg/kg”, wherein dosages may be administered daily, every other day, biweekly, or weekly (see, e.g., WO’558 at ¶[0075], claims 16-18, 20) 6. Accordingly, the prior art taught and directed artisans to treat the same disease using the same compound at the same or overlapping dosage and dosage frequency. Accordingly, such limitations do not weigh in favor of a determination of obviousness, because they were known in the prior art, and would merely yield the expected and predicted results taught by the prior art, namely treatment of GvHD (e.g., acute GvHD).
The primary reference differs from the claimed invention as follows: Although WO’558 generally teaches the administration of overlapping dosages and dosing frequencies of the same compounds to the same patient population as presently claimed, WO’558 does not reduce to practice a species having the specific dosing regimen presently claimed.
However, as noted above, WO’558 teaches methods of treating patients for all forms of GvHD, including acute GvHD, including in patients following HCT procedures, by administering steroids (e.g., prednisone) and AAT for 1-60 days, wherein AAT is administered at “about 1.0 mg/kg to about 150 mg/kg” biweekly (see, e.g., WO’558 at ¶¶[0010]-[0011], [0018], [0044], [0050] [0075], claims 16-18, 20)7, wherein administration of AAT may be adjusted “according to the individual need” as “determined by a health professional” (see, e.g., WO’558 at ¶[0075]). Furthermore, WO’558 identifies the predicted and expected result of such treatment, namely administration of AAT would:
“reduce production of pro-inflammatory cytokines, induce anti-inflammatory cytokines and interfere with maturation of dendritic cells”
(see, e.g., WO’558 at ¶[0056]).
Furthermore, WO’558 informs artisans that
....a recipient subject can be administered the composition before, during or after, or combination of before, during and after transplantation in order to reduce transplantation rejection and/or GvHD in the subject. Compositions disclosed herein can be administered to the subject . . . according to any of the regimens described herein.
(see, e.g., WO’558 at ¶[0047]).
The “composition” referred to by WO’558 (see id) is understood to be AAT (Alpha-1 antitrypsin) ranging in “therapeutically effective amounts” from “about 1.0 to about 150 mg/kg” sufficient to “maintain a predetermined blood concentration of AAT (e.g., 2.0 to 4.0 mg/mL)” (see, e.g., WO’558 at ¶[0017], emphasis added). WO’558 informs artisans that
Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 1.0-150 mg/kg of the active ingredient(s).
(see, e.g., WO’558 at ¶[0080]).
The “intermittent infusions” would be reasonably inferred to mean the dosages administered according as necessary to maintain the desired blood levels (see id.). WO’558 identifies that doses may be
...administered multiple times a day, daily, every other day, biweekly, weekly, monthly etc.
(see, e.g., WO’558 at ¶[0075]).
Regarding the duration of treatment, WO’558 informs artisans that treatment may range from
“5 to 60 day[s] or longer . . . . depending on need”
(see, e.g., WO’558 at ¶[0011]).
Regarding the initial or loading dosage, WO’558 informs artisans that the initial dosage may be
“1.5 to 10 times . . higher AAT . . . concentration than the one or more follow-on doses”
(see, e.g., WO’558 at ¶[0037]).
The predicted and expected effects of such treatment regimes would include the cytokine benefits mentioned above (see, e.g., WO’558 at ¶[0056]), which would predictably lead to the treatment of GvHD (and/or acute GvHD) by maintaining AAT at desirable blood levels (see, e.g., WO’558 at ¶[0080]). In addition, WO’558 informs artisans that the disclosed embodiments are applicable to patients that are matched or mismatched with respect to HLA (see, e.g., WO’558 at ¶¶[0047], claims 27-28; see also id. at ¶[0056], describing allogeneic BMT and HCT; see also id. at ¶[00127], describing allogeneic HCT recipients).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): First, the invention is the combination of known prior art elements according to known methods of treating acute GvHD as taught by the primary reference, wherein such combination merely produces the predicted and expected result, namely treatment of acute GvHD, and wherein each component merely performs its art-recognized function (see, e.g., MPEP § 2143(I)(A), (C), (D)). In addition or alternatively, the claimed invention appears to be a prior art method, using prior art dosages, dosing frequencies, compounds, and patient populations, but wherein the instant claims are directed to presumably an optimized method within the ranges taught by the prior art. However, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Per MPEP § 2144.05(II), differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. Here, no evidence of criticality or unexpected results have been identified on record commensurate in scope with the requirements of MPEP § 716.02. Therefore, since Applicant has not disclosed that the specific limitations recited in the instant claims pertaining to dosage frequency and dosage amount are for any particular purpose or solve any stated problem and the prior art teaches that dosage and dosing frequency may vary over the claimed range, wherein such dosages and dosing frequencies are result-effective variables utilized to obtain and maintain “[d]esirable blood levels” of AAT at “2.0 to 4.0 mg/mL” in patients in need of treatment of acute GvHD following a HCT to treat or prevent acute GvHD by predictably and expectedly reducing production of pro-inflammatory cytokines, inducing anti-inflammatory cytokines and interfering with maturation of dendritic cells (see, e.g., WO’558 at ¶[0056]), and such parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the AAT arts.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Accordingly, administering known compounds to a known patient population, for known durations at known concentrations would predictably and expectedly yield the results taught and disclosed by the prior art, namely the treatment of GvHD, including acute GvHD.
Accordingly, claims 50, 53, 62-63, 71 and 74 are rejected.
Response to Arguments
Applicant's arguments filed 3/27/2026 have been fully considered but they are not persuasive as explained below. It is the Examiner’s understanding that Applicant traverses the rejection under 35 USC 103 for the reasons discussed at pages 6-14 (see, e.g., Reply filed 3/27/2026 at 6 at § 35 U.S.C. § 103 to page 14 at final full ¶). These arguments are addressed below.
Applicant provides partial summary of rejection: It is the Examiner’s understanding that Applicant summarizes the rejection (see, e.g., Reply filed 3/27/2026 at 6 at § 35 U.S.C. § 103 to page 7 at 1st partial ¶). Examiner notes that the summary fails to capture the nuances of the rejection, including supporting citations and quotations; therefore, Examiner directs Applicant to the rejection, maintained above.
Applicant alleges lack of motivation to arrive at the claimed invention: It is the Examiner’s understanding that Applicant is alleging that there is no motivation for an artisan to arrive at the specific claimed dosage regimen now claimed, because “a similar dosage to the one that Dinarello focused on in its Examples would not achieve the target median trough plasma level of A1AT” (see, e.g., Reply filed 3/27/2026 at 7 at 1st full ¶, 14 at 2nd full ¶ starting with “In summary”). This is not persuasive for the following reasons:
First, obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Here, the Examiner expressly provides multiple rationales supporting a determination of obviousness, which are explicitly identified on record, namely rationales under MPEP § 2143(I)(A), (C), (D), and MPEP § 2144.05(II). Therefore, rationales supporting a determination of obviousness are explicitly set forth on record.
Second, the premise that “a similar dosage to the one that Dinarello focused on in its Examples would not achieve the target median trough plasma level of A1AT” (see, e.g., Reply filed 3/27/2026 at 7 at 1st full ¶) is not persuasive because it fails to reflect US patent prosecution practice since the primary reference is not limited to a dosage “focused on in its Examples”; rather, the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Accordingly, arguments premised upon simply dismissing the full teachings of the prior art, and only considering limited portions of exemplified embodiments, are not persuasive.
Third, Applicant’s argument references an unclaimed limitation (see, e.g., Reply filed 3/27/2026 at 7 at 1st full ¶, referring to “the target median trough plasma level of A1AT”). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “the target median trough plasma level of A1AT”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Accordingly, such limitations doe not patentably distinguish the claimed invention over the prior art.
Accordingly, such arguments are not persuasive because there are clear motivations supporting a determination of obviousness set forth in the rejection (e.g., MPEP §§ 2143(I)(A), (C), (D), and MPEP § 2144.05(II)), the prior art is not limited to exemplified embodiments, and the argument is premised upon an unclaimed limitation.
Applicant refers to a Declaration by David Gossage: It is the Examiner’s understanding that Applicant’s arguments rely, at least in part, upon a Declaration by David Gossage filed 3/27/2026 (see, e.g., Reply filed 3/27/2026 at 7 at 1st full ¶, 7 at final ¶ to 8 at 1st full ¶, 8 at final ¶, 9 at §§ “1. Recited dosage…” to 10 at 1st full ¶, 10 at §§ “2. Recited dosage….” to page 14 at 1st full ¶ starting with “As noted in the Declaration”). The Declaration, and all statements and evidence therein, has been considered in a separate section below. In brief, the Declaration fails to rebut prima facie obviousness by establishing unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, skepticism of experts, or inoperability. Therefore, all arguments relying upon the Declaration, evidence set forth therein, or statements set forth in the Declaration, have been fully considered but not found persuasive.
Findings in the prior art teachings as relied upon in the rejection were not disputed with specificity: As discussed in the rejection, WO’558 does in fact teach and disclose methods of treating the same patient populations with the same compounds at the same or overlapping dosages administered at the same or overlapping frequencies, to achieve the same outcome, namely successful treatment of acute GvHD, wherein an artisan would optimize the doses, dosing frequencies, and treatment durations to achieve and maintain “[d]esirable blood levels” of AAT at “2.0 to 4.0 mg/mL” in such patients, which would treat acute GvHD by predictably and expectedly reducing production of pro-inflammatory cytokines, inducing anti-inflammatory cytokines, and interfering with maturation of dendritic cells (see, e.g., WO’558 at ¶[0056]). Applicant does not dispute nor address these teachings, as relied upon by the Examiner. Examiner notes that such undisputed determinations are sufficient to support determinations of obviousness based upon exemplary rationales set forth in the MPEP, including MPEP §§ 2143(I)(A), (C), (D), and MPEP § 2144.05(II).
Applicant alleges that there is “No suggestion in Dinarello of the claimed dosage regimen or duration of treatment”: Although Applicant alleges that this is “No suggestion in Dinarello of the claimed dosage regimen or duration of treatment” (see, e.g., Reply filed 3/27/2026 at 7 at §§ “A”; see also Reply filed 9/10/2025 at 7-9 at §§ A), Applicant subsequently admits and acknowledges that the primary reference does, in fact, teach the claimed dose range, dosing frequencies, and treatment durations (see, e.g., Reply filed 3/27/2026 at 7 at final ¶ to 8 at 1st full ¶; see also Reply filed 9/10/2025 at 7 at final full ¶ to 8 at final full ¶). Accordingly, by Applicant’s own admission, the prior art does in fact teach and direct artisans to administer the same compound (i.e., A1AT) at an overlapping dosage (e.g., “about 1.0 to about 150 mg/kg”), an overlapping dosage frequency (i.e., ranging from “multiple times a day, daily, ever other day, biweekly, weekly, monthly, etc.”), at an overlapping treatment duration (i.e., ranging from “5 to 60 day[s] or longer…depending on need”), to the same patient population (i.e., patients in need of treatment for acute GVHD) (see, e.g., Reply filed 3/27/2026 at 7 at final ¶ to 8 at 1st full ¶; see also Reply filed 9/10/2025 at 7 at final full ¶ to 8 at final full ¶). Examiner previously noted such admissions on record (see, e.g., Action mailed 10/27/2025 at 12-13 at bridging ¶) and explained that, per MPEP § 2144.05(I), in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (see, e.g., Action mailed 10/27/2025 at 13 at 1st full ¶), but Applicant failed to directly respond in the most recent reply filed 3/27/2026. Accordingly, such arguments are not persuasive because the prior art clearly directs artisans to treat the same patient population with the same compounds at the same (or overlapping) dosages, dosage frequencies, and treatment durations, in order to achieve a known outcome. Evidence showing that the prior art disclosure was, in fact, enabled for what it disclosed supports a determination of obviousness rather than non-obviousness (see, e.g., MPEP § 716.02(c)(II), explaining that evidence of expected beneficial results is evidence supporting a determination of obviousness).
Applicant alleges that the ranges taught by the primary reference are “very broad” and that the primary reference “does not provide sufficient guidance to derive the claimed dosages and schedule”: Regarding the Applicant’s opinion that the prior art teachings are “very broad” and the allegation that the primary reference “does not provide sufficient guidance to derive the claimed dosage and schedule” (see, e.g., Reply filed 3/27/2026 at 7-8 at §§ A, 7 at final ¶, 8 at 1st full ¶ starting with “Therefore”), as noted in the preceding paragraph the prior art provides explicit guidance directing artisans to administer the same compound (i.e., A1AT) at an overlapping dosage (e.g., “about 1.0 to about 150 mg/kg”), an overlapping dosage frequency (i.e., ranging from “multiple times a day, daily, ever other day, biweekly, weekly, monthly, etc.”), at an overlapping treatment duration (i.e., ranging from “5 to 60 day[s] or longer…depending on need”), to the same patient population (i.e., patients in need of treatment for acute GVHD), wherein per MPEP § 2144.05(I), in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. However, it is the Examiner’s understanding that Applicant opines that such ranges are “very broad” and would not permit an artisan to “derive the claimed dosages and schedule” as presently claimed, even though the claimed dosages and schedule fall directly within the disclosed ranges explicitly taught by the prior art. In the absence of clarification, presumably, Applicant is alleging that (i) the prior art is not fully enabled or operable, (ii) skepticism of experts, or (iii) that it is not within the ability of an artisan to optimize the parameters disclosed by the prior art. These are addressed below:
Regarding (i), the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Accordingly, the full scope of ranges taught by the prior art are presumed to be fully enabled absent objective evidence to the contrary. Evidence to the contrary must satisfy the requirements set forth at MPEP §§ 716, 716.01, and 716.07. Here, no showing commensurate with MPEP § 716.07 has been placed on record showing any inoperability or lack of enablement of the prior art, or otherwise providing a comparison of alleged inoperable features with the instant disclosure. Accordingly, if such an argument is being made, it is not persuasive.
Regarding (ii), if Applicant is attempting to allege the existence of skepticism of experts regarding the disclosure of the primary reference, evidence commensurate in scope with the requirements set forth at MPEP §§ 716, 716.01, and 716.05 must be placed on record. Here, no evidence of any skepticism of experts “expressed before these inventors proved him wrong” has been set forth or identified on record (see, e.g., MPEP § 716.05). Rather, the prior art teaches that there would be no skepticism since the prior art teaches the same method of treating the same patient population with the same compounds at the same (or overlapping) dosages, dosage frequencies, and treatment durations to achieve the same outcome, and such prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Rather, the evidence of record shows that an embodiment within the scope of the prior art works exactly as expected (see, e.g., Dec., passim), which supports a determination of obviousness (see, e.g., MPEP § 716.02(c)(II), explaining that evidence of expected beneficial results is evidence supporting a determination of obviousness). Accordingly, no evidence of skepticism by experts has been placed on record.
Regarding (iii), if Applicant is alleging that, although WO’558 does in fact teach and direct artisans to practice the same methods, on the same patient populations, using the same compound, at the same or overlapping dosages, and at the same or overlapping frequencies (see, e.g., WO’558 at ¶¶[0010]-[0011], [0018], [0037], [0044], [0050] [0075], [0080], claims 16-18, 20)8, that an artisan would not be able to optimize such parameters to arrive at the instant claimed invention, then this argument is not persuasive because the case law is clear that "No invention is involved in discovering optimum ranges of a process by routine experimentation." (see, e.g., Application of Aller, 220 F.2d 454, 458, 105 USPQ 233, 236-237 (C.C.P.A. 1955)) and that the "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Here, the prior art of WO’558 also provides guidance to a therapeutic endpoint permitting an artisan to optimize parameters impacting blood levels of AAT (i.e., dosage, dosage frequency, treatment duration); namely, WO’558 provides guidance directing artisans to methods that would obtain and maintain “[d]esirable blood levels” of AAT at “2.0 to 4.0 mg/mL” in patients in need of treatment of acute GvHD following a HCT to treat or prevent acute GvHD (see, e.g., WO’558 at ¶[0017]), wherein such blood levels would yield predictable results (see, e.g., WO’558 at ¶[0056]).
In sum, allegations that the ranges taught by the prior art are “very broad”, made in the absence of any evidence of any criticality of ranges or unexpected results, is not persuasive as explained above, because it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the AAT arts (see MPEP § 2144.05(II)), and per MPEP § 2144.05(I), in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Allegations of unexpected results: It is the Examiner’s understanding that Applicant alleges the existence of “Surprisingly excellent results for the claimed dosage/duration regimen”, and that “The success of the claimed regimen would not have been expected based on the teachings of Dinarello” (see, e.g., Reply filed 3/27/2026 at pages 8-14 at §§ B, 14 at 2nd full ¶ starting with “In summary”), but the basis for these statements are unclear because the proffered data appears to show the expected and predicted results disclosed by the prior art (see, e.g., MPEP § 716.02(c)(II), explaining that evidence of expected beneficial results is evidence supporting a determination of obviousness). Accordingly, the proffered data appears to show the exact outcome expected and predicted in view of the primary reference, namely that by administering the same compound (i.e., A1AT) at an overlapping dosage (e.g., “about 1.0 to about 150 mg/kg”), an overlapping dosage frequency (i.e., ranging from “multiple times a day, daily, ever other day, biweekly, weekly, monthly, etc.”), at an overlapping treatment duration (i.e., ranging from “5 to 60 day[s] or longer…depending on need”), to the same patient population (i.e., patients in need of treatment for acute GVHD), the method would predictably, expectedly, desirably, and beneficially yield the exact outcomes disclosed by the prior art, namely the successful treatment of acute GvHD following a HCT to treat or prevent acute GvHD (see, e.g., WO’558 at ¶[0017]), among other predictable results (see, e.g., WO’558 at ¶[0056]). Accordingly, for the Examiner it is prima facie unclear what portion of the proffered data would be “surprising” or “would not have been expected” in view of the prior art of record, and therefore such statements and allegations appeared to be unsupported by objective evidence. The statements of the Declarant and proffered evidence set forth in the Declaration have been separately considered below. In brief, the proffered evidence fails to establish unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, because the proffered data appears to simply confirm the expectations set forth in the prior art9, fails to establish the existence of skepticism of experts or inoperability of the prior art10, and fails to establish criticality of range per MPEP § 716.02(d).
Applicant has potentially discovered additional benefits that flow from following the guidance of the prior art: It is the Examiner’s understanding that Applicant proffers data showing that following the guidance of the prior art by administering the same compound (i.e., A1AT) at an overlapping dosage (e.g., “about 1.0 to about 150 mg/kg”), an overlapping dosage frequency (i.e., ranging from “multiple times a day, daily, ever other day, biweekly, weekly, monthly, etc.”), at an overlapping treatment duration (i.e., ranging from “5 to 60 day[s] or longer…depending on need”), to the same patient population (i.e., patients in need of treatment for acute GVHD, may yield additional benefits not recognized explicitly by the primary reference (e.g., it “did not increase the risk of infections” at Reply filed 3/27/2026 at page 11 at 1st full ¶). In response to applicant's argument that following the guidance of the prior art yields additional benefits, not contemplated by the prior art, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The disclosure of other potential dosages, dosage frequencies, and treatment durations suitable for obtaining an AAT blood level of 2.0-4.0 mg/mL do not amount to a “teaching away”: It is the Examiner’s understanding that Applicant is suggesting that the broad disclosure of the prior art pertaining to unclaimed methods somehow “teaches away” from the claimed invention (see, e.g., Reply filed 3/27/2026 at 7 at 1st full ¶, 8 at 1st partial ¶). This is not persuasive or correct because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, the prior art reference at issue does not “teach away” from its own disclosure as it does not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)).
The weight of evidence of record, considered as a whole, weighs in favor of a determination of obviousness: Here, the prior art teaches methods of treating acute GVHD by administering to a patient a steroid and A1AT, wherein the prior art teaches administration of the same compounds at the same (or overlapping) dosages, dosage frequencies, and treatment durations to achieve the same outcome, and such prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). The proffered data appears to merely yield the predicted and expected results taught by the prior art, namely that such methods could be utilized to maintain “[d]esirable blood levels” of AAT within patients (i.e., “2.0 to 4.0 mg/mL”) in need of treatment of acute GvHD following a HCT to treat or prevent acute GvHD (see, e.g., WO’558 at ¶[0017]), and wherein such blood levels would yield predictable results (see, e.g., WO’558 at ¶[0056]). Applicant has offered no objective supporting evidence of unexpected results, skepticism of experts, or inoperability of the prior art commensurate in scope with the requirements of MPEP §§ 716.02, 716.05, and 716.07. The Court has stated that
A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007).
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Here, all aspects of the claimed method were already known in the art, including the patient population, compounds, dosages, dosage frequencies, and the predicted and expected outcome of such methods. Furthermore, at best, Applicant may have found the optimal dosage and dosage frequency within the prior art ranges; however, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955) because "[n]o invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. Accordingly, the mere fact that the prior art teaches a multiple concentrations and dosage frequencies do not weigh in Applicant’s favor because there is a reasonable expectation of success for all such concentrations and dosages because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)).
Accordingly, all arguments raised by the Applicant has been fully considered but not found persuasive for the reasons set forth above. Therefore, the rejection of record is maintained and no claims are in form for allowance.
Response to Declarations of David Gossage under 37 C.F.R. §1.132
The affidavit under 37 CFR 1.132 filed 3/27/2026 is insufficient to overcome the rejections of record. A detailed explanation of why the affidavits or declarations are insufficient is provided below. The legal standards of review and consideration of Declarations under 37 C.F.R. §1.132 are discussed at MPEP § 716.01.
Interest of the Expert in the Outcome of the Case
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the interest of the expert in the outcome of the case. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 227 USPQ 657 (Fed. Cir. 1985), cert, denied, 475 U.S. 1017 (1986). Here, David Gossage is an employee of the Applicant (see, e.g., Dec. filed 3/27/2026 at ¶1) and therefore has a clear interest in the outcome of the case.
Nature of the Matter Sought to be Established
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established. Ashland Oil, Inc., 776 F.2d 281.
Here, it is understood that the Declarant seeks to establish
(i) unexpected results commensurate in scope with the requirements set forth at MPEP § 716.02 (see, e.g., Reply filed 3/27/2026 at 8 at §§ B, 14 at 1st partial ¶ to 2nd full ¶; see, e.g., Dec. filed 3/27/2026 at ¶24);
(ii) inoperability of the prior art regarding optimization of ranges as set forth at MPEP § 716.07 (see, e.g., Reply filed 3/27/2026 at 7-8 at §§ A, 7 at final ¶, 8 at 1st full ¶ starting with “Therefore”, discussing lack of guidance of prior art; see, e.g., Dec. filed 3/27/2026 at ¶5 and ¶24);
(iii) skepticism of expert as set forth at MPEP § 716.05 (see, e.g., Reply filed 3/27/2026 at 7-8 at §§ A, 7 at final ¶, 8 at 1st full ¶ starting with “Therefore”, discussing lack of guidance of prior art; see, e.g., Dec. filed 3/27/2026 at ¶5 and ¶24); and
(iv) opinion evidence as set forth at MPEP § 716.01(c)(III) (see, e.g., Dec. filed 3/27/2026 at ¶¶5-6, 16, 24).
The legal requirements for establishing unexpected results, inoperability of the prior art, skepticism of experts, or opinion evidence sufficient to rebut prima facie obviousness is discussed below.
Opinions as to Legal Conclusions
As an initial matter, Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been fully considered as detailed below.
Presence or absence of factual support for the expert’s opinion
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the presence or absence of factual support for the expert’s opinion. Ashland Oil, Inc., 776 F.2d 281.
Allegations of Unexpected Results
To establish unexpected results, the proffered evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art invention(s) of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP § 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)).
Here, the proffered data is understood to correspond to the results and designs of NCT04167514 (see, e.g., Dec. filed 3/27/2026 at ¶¶6-23). However, such data fails to satisfy the requirements of MPEP § 716.02 as follows:
First, the proffered evidence does not establish unexpected results or otherwise that expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), wherein a comparison of the invention as actually claimed is compared with the closest prior art invention of record (see, e.g., MPEP § 716.02(e)). Rather, the proffered data, conclusions, and alleged statistical significance (or lack thereof) is premised upon a comparison with a placebo rather than the closest prior art of record (see, e.g., Dec. filed 3/27/2026 at ¶¶6-23).The closest prior art of record discloses examples wherein AAT (GLASSIA®) is administered to patients (see, e.g., WO’558 at ¶¶[00129])11.
Second, the proffered evidence must establish that any alleged expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), wherein all proffered data is fully explained (see, e.g., MPEP § 716.02(b)(II)). Here, the proffered data appears to pertain to an unclaimed invention, having numerous unclaimed parameters, which are of unknown relevance to the invention as presently claimed (see, e.g., Dec. filed 3/27/2026 at ¶¶6-23, reciting and referring to unclaimed limitations and parameters such as loading doses, “median target plasma trough levels”, “GI losses”, “desired goal concentrations by day 8”, “overall response rate (ORR)”, “complete response (CR)”, “partial response (PR)”, “maximum aGVHD organ stage”, “duration of response (DOR)”, “next line therapy (NLT)”, “flare”, “non-relapse mortality (NRM)”, “GVHD-free survival”, “Intention to treat (ITT)”, “grade 3-5 adverse events”, “Mount Sinai aGVHD International Consortium's (MAGIC) serum biomarker panel of suppressor of tumorigenicity (ST2) and regenerating islet-derived protein 3-alpha (Reg 3α)”, “MAGIC”, “Refined Minnesota High Risk GVHD”, “MAGIC biomarker risk scores”, “placebo arm”, “potential effect of the MAGIC biomarker risk”, “incidence of chronic GVHD at 1 year”, “high-risk biomarker scores”, ruxolitinib, “salvage therapy”, “Crypt damage”, etc., etc.). In response, it is noted that, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Accordingly, such data is proffered without meaningful explanation of why such results with such unclaimed parameters render the invention as actually claimed less obvious in view of the disclosure of the primary reference.
Third, the proffered data pertains to an unclaimed species comprising a loading dose at 180 mg/kg, which is not recited nor required by the pending claims (see, e.g., Dec filed 3/27/2026 at ¶8). Evidence commensurate in scope with the requirements of MPEP § 716.02 must provide a comparison of the “claimed invention” (see, e.g., MPEP §§ 716.02(b)(III), 716.02(c), 716.02(d), 716.02(e)(I), 716.02(e)(III)). Here, the invention as actually claimed is not tested; this is pertinent because although a loading dose of 180 mg/kg is permissible in view of the open-ended nature of instant claim 50, the additional treatment fails to represent results commensurate in scope with the invention as actually claimed per MPEP § 716.02(d). Furthermore, the proffered data is not commensurate in scope to the pending claims because claim 50 is not limited to allogeneic HCT, methods requiring 2 mg/kg/day of prednisone, etc. (see, e.g., MPEP § 716.02(d)). No explanation of why any alleged observation of unexpected results made relative to a placebo in the limited conditions tested in the proffered data could be reasonably extended to untested compounds, untested concentrations, and untested patient populations was set forth in the instant Declaration.
Fourth, no criticality of range per MPEP § 716.02(d)(II) has been established. This is pertinent because the prior art of record teachings the administration of the same compounds to the same patient population at the same overlapping dosages, dosage frequencies, and treatment durations, and zero evidence currently supports that treatments of 120 mg/kg form a critical range by providing a comparison of “a sufficient number of tests both inside and outside the claimed range” (see, e.g., MPEP § 716.02(d)(II)).
Fifth, the proffered data does not unambiguously establish or identify any unexpected results or establish that an expected result occurs to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), because the proffered results appear to show expected and predicted results taught by WO’558 as summarized in the rejection above. WO’558 pertains to the treatment of subjects having GvHD, acute GvHD, GvHD that is steroid-refractory acute GvHD, (see, e.g., WO’558 at abs, ¶¶[0007]-[0008], [0015], [0040], [0056]), including patients at risk of acute GvHD, which is a “major complication” of allogeneic HCT (see, e.g., WO’558 at ¶[0056]), wherein treatment of all such patients includes administration of the same compounds as presently claimed, administered at overlapping concentration ranges and overlapping frequency and duration ranges (see, e.g., WO’558 at title, abs, claims 16-18, 20, ¶¶[0008], [0011], [0075]; see also, rejection above). The predicted and expected results of such prior art treatment was clearly identified by WO’558, namely such treatment would:
“reduce production of pro-inflammatory cytokines, induce anti-inflammatory cytokines and interfere with maturation of dendritic cells”
(see, e.g., WO’558 at ¶[0056]; see also id. at title, abs).
Accordingly, the predicted and expected result would be the successful treatment of GvHD, exactly as shown in the proffered data. Critically, showing proffered evidence that confirms the predicted and expected results of the prior art is evidence of obviousness rather than non-obviousness (see, e.g., MPEP § 716.02(c)(II)). Accordingly, it is unclear what exact results are “unexpected”, “surprising”, or not consistent with the expectations set forth in WO’558.
In sum, the proffered data is insufficient to establish a showing of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, and sufficient to rebut prima facie obviousness because the proffered data does not satisfy the requirements of at least MPEP § 716.02(b)(I), § 716.02(b)(II), § 716.02(d), and § 716.02(e); rather, the proffered data appears to confirm the predicted and expected results of the prior art, which weighs in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). Accordingly, per MPEP § 716.01(d) and § 716.02(c), in view of prior art teaching the same compounds administered to the same or overlapping patient population at the same or overlapping concentrations, frequencies, and durations, wherein the prior art identifies multiple advantages of such treatments that appear to be confirmed by the proffered data, the evidence of record weighs in favor of a determination of obviousness. Accordingly, all arguments premised upon allegations of unexpected results have been fully considered, but not found persuasive.
Allegations of Inoperability of the Prior Art
It is the Examiner’s understanding that Declarant is alleging that the primary reference is not fully enabled for the full scope of dosages, dosage frequencies, and treatment durations disclosed therein because the Declarant provides an opinion alleging that “Dinarello does not suggest any dosage regimens that could have these effects” see, e.g., Reply filed 3/27/2026 at 7-8 at §§ A, 7 at final ¶, 8 at 1st full ¶ starting with “Therefore”, discussing lack of guidance of prior art; see, e.g., Dec. filed 3/27/2026 at ¶5 and ¶24). Declarant fails to elaborate or explain why the disclosure of WO’558, as cited by the Examiner in the rejection, would not directly lead an artisan to methods of treating the same patient population by administering the same compounds at the same (or overlapping) dosages, dosing frequencies, and treatment durations, wherein such methods would predictably lead to blood levels of AAT at 2.0-4.0 mg/kg, thereby treating aGVHD patients. In the absence of clarification, such statements have been presumed to be an allegation that WO’558 is not fully enabled or operable.
A showing of inoperability sufficient to rebut obviousness is discussed at MPEP § 716.07. Here, the prior art of WO’558 is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)), and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I)).
Here, the Declarant fails to “rebut the presumption of operability by a preponderance of the evidence” as required by MPEP § 716.07, because the Declarant fails to identify any portion or teaching of WO’558 relied upon by the Examiner that was not fully operable and enabling, and fails to proffer any objective evidence that any portion of WO’558 is, in fact, inoperable or not enabled.
Furthermore, per MPEP § 716.07, “Where the affidavit or declaration presented asserts that the reference relied upon is inoperative, the claims represented by applicant must distinguish from the alleged inoperative reference disclosure”, but in the instant case the claims are directed to the same invention as presently claimed, wherein the same compounds are administered to the same patient population at the same (or overlapping) dosages, dosage frequencies, and treatment durations.
Accordingly, the Declarant’s arguments fail to satisfy the requirements of MPEP § 716.07.
Allegations of Skepticism of Experts
It is the Examiner’s understanding that Declarant is alleging that the disclosure of the primary reference regarding dosages, dosage frequencies, and treatment durations was met by skepticism of experts because the Declarant provides an opinion alleging that “Dinarello does not suggest any dosage regimens that could have these effects” (see, e.g., Reply filed 3/27/2026 at 7-8 at §§ A, 7 at final ¶, 8 at 1st full ¶ starting with “Therefore”, discussing lack of guidance of prior art; see, e.g., Dec. filed 3/27/2026 at ¶5 and ¶24). Declarant fails to elaborate or explain why the disclosure of WO’558, as cited by the Examiner in the rejection, would not directly lead an artisan to methods of treating the same patient population by administering the same compounds at the same (or overlapping) dosages, dosing frequencies, and treatment durations, wherein such methods would predictably lead to blood levels of AAT at 2.0-4.0 mg/kg, thereby treating aGVHD patients. In the absence of clarification, such statements have been presumed to be an allegation that the relevant disclosure of WO’558 would be met by skepticism of experts.
A showing of skepticism of experts sufficient to rebut obviousness is discussed at MPEP § 716.05, which explains that "Expressions of disbelief by experts constitute strong evidence of nonobviousness" and that "The skepticism of an expert, expressed before these inventors proved him wrong, is entitled to fair evidentiary weight” (see, e.g., MPEP § 716.05).
Here, the prior art of WO’558 is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). The burden is on the Applicant to establish skepticism of experts (see, e.g., MPEP § 716.05).
Here, the Declarant fails to establish the existence of any skepticism of experts supported by any citation to printed or published literature relevant to the pending claimed invention. Accordingly, the Declarant fails to identify any portion or teaching of WO’558 relied upon by the Examiner that was met by skepticism by any expert.
Accordingly, the Declarant’s arguments fail to satisfy the requirements of MPEP § 716.05.
Allegations of Skepticism of Experts
It is the Examiner’s understanding that Declarant provides opinion evidence regarding the obviousness of the claimed invention in view of WO’558 (see, e.g., Dec. filed 3/27/2026 at ¶¶5-6, 24). Specifically, the Declarant alleges
The Examples of Dinarello, however, focus on dosage of 90 mg/kg on day l and follow-on doses of 30 mg/kg or 60 mg/kg. See Dinarello [0012], [0037], and examples. Thus, in my opinion, Dinarello does not provide sufficient guidance to derive the specific, claimed dosages and schedule.
(see, e.g., Dec. filed 3/27/2026 at ¶5).
It was found that the claimed dosing regimen of A1AT with a corticosteroid provided a safe and effective therapy to treat patients with aGVHD after HCT procedure, despite some challenges to the study (which are discussed below). This would not have been expected based on the teachings of Dinarello, as Dinarello does not provide any guidance for the claimed dosing regimen (see ¶ 4).
(see, e.g., Dec. filed 3/27/2026 at ¶6).
These results could not have been expected from Dinarello, as Dinarello does not suggest any dosage regimens that could have these effects.
(see, e.g., Dec. filed 3/27/2026 at ¶24).
Regarding opinion evidence, MPEP § 716.01(c)(III) explains that opinion evidence is fully considered primarily based upon the provided factual evidence supporting the opinion (see, e.g., MPEP § 716.01(c)(III), explaining that the need to consider “the presence or absence of factual support for the expert’s opinion”, and noting that an “expert opinion” was “inadequate to overcome the rejection based on that prior art because there was no factual evidence supporting the statement” of the expert).
Upon inspection, the Declarant’s opinions appear unsupported by any objective, factual evidence (see, e.g., Dec. filed 3/27/2026 at ¶¶5-6, 24), because such statements appear conclusory in nature and fail to meaningfully explain why the teachings of WO’558 would be deemed insufficient, inoperable, or otherwise met with skepticism. As noted above, the prior art of WO’558 is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “nonpreferred and alternative embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Here, the prior art explicitly teaches methods of treating the same patient population by administering the same compounds at the same (or overlapping) dosage, dosage frequency, and treatment duration, in order to achieve the same result (i.e., treatment of acute GVHD); this is pertinent because Declarant fails to provide any supporting evidence that such explicit guidance by the prior art is insufficient to guide an artisan to perform the exact methods disclosed by the prior art in order to achieve the exact results taught by the prior art.
It is noted that the Declarant refers to an unclaimed limitation, namely the treatment of NCT04167514 targeted treatments that “target[ed] A1AT concentrations that approached the upper limits of normal (250 mg/dL)” (see, e.g., Dec. at ¶8), and that the “mean trough level” corresponded to a “target 250 mg/dL” (see, e.g., Dec. at ¶10). This is pertinent because “250 mg/dL” is 2.5 mg/mL, and therefore the “targeted” blood level of A1AT in the proffered data falls within the targeted range taught and disclosed by WO’558 (see, e.g., WO’558 at ¶¶[064]-[065], [071], noting that WO’558 explicitly discloses and directs artisans to receive “a dosage level” sufficient to “provide an average or median peak serum A1AT level” at “2.5 mg/mL” or between 2 and 4 mg/mL). Accordingly, not only does the prior art teach methods of treating the same patient population with the same compounds at the same (or overlapping) dosages, dosage frequencies, and treatment durations, but also discloses the same overlapping therapeutic endpoint level of serum A1AT that patients should have to effect treatment. In view of such high similarity, it is prima facie unclear how the prior art of WO’558 would not provide an artisan with sufficient guidance to arrive at the claimed invention via routine methods of optimizing known methods using known compounds within known ranges to achieve known results having a known therapeutic endpoint.
The Examiner has reviewed the Declaration and notes that the pending claims and teachings of the primary reference are only mentioned at paragraphs 2-3, 5-6, and 24 of the Declaration, using conclusory statements or otherwise merely referring to the rejection of record generally (see, e.g., Dec. filed 3/27/2026 at ¶¶5-6, 24). However, the bulk of the declaration focuses upon the results and designs of NCT04167514 (see, e.g., Dec. filed 3/27/2026 at ¶¶6-23), wherein the discussion pertains to unclaimed limitations and parameters such as loading doses, “median target plasma trough levels”, “GI losses”, “desired goal concentrations by day 8”, “overall response rate (ORR)”, “complete response (CR)”, “partial response (PR)”, “maximum aGVHD organ stage”, “duration of response (DOR)”, “next line therapy (NLT)”, “flare”, “non-relapse mortality (NRM)”, “GVHD-free survival”, “Intention to treat (ITT)”, “grade 3-5 adverse events”, “Mount Sinai aGVHD International Consortium's (MAGIC) serum biomarker panel of suppressor of tumorigenicity (ST2) and regenerating islet-derived protein 3-alpha (Reg 3α)”, “MAGIC”, “Refined Minnesota High Risk GVHD”, “MAGIC biomarker risk scores”, “placebo arm”, “potential effect of the MAGIC biomarker risk”, “incidence of chronic GVHD at 1 year”, “high-risk biomarker scores”, ruxolitinib, “salvage therapy”, “Crypt damage”, etc., etc. (see, e.g., Dec. filed 3/27/2026 at ¶¶6-23). These recitations directed to unclaimed limitations fail to meaningfully distinguish how the claimed invention differs from the prior art of record.
Accordingly, the Declarant’s conclusory statements are unsupported by objective evidence and appear to be directly contradicted by the evidence of record, including the teachings of the primary reference explicitly cited in the rejection, which were not considered or addressed by the declarant.
Weighing Objective Evidence
Per MPEP § 716.01(d), the ultimate determination of patentability must be based on consideration of the entire record and notes that submission of evidence of patentability does not mandate a conclusion of patentability in and of itself. Accordingly, the Declaration has been fully considered but is not found persuasive because it does not establish unexpected results, inoperability of WO’558, skepticism of experts, or otherwise provide any objective evidence supporting the Declarant’s conclusory opinions commensurate in scope with the requirements set forth in the MPEP (see, e.g., MPEP §§ 716.01, 716.02, 716.05, 716.07). Therefore, in view of the record as a whole, the Declaration is insufficient to overcome the rejection of record, which are maintained as set forth above.
Here, the claimed invention is understood to be directly within the scope of the prior art, wherein the prior art teaches the same methods of treating the same patient population with the same compounds at the same (or overlapping) dosages, dosage frequencies, and treatment durations, and wherein the prior art also discloses the same overlapping therapeutic endpoint level of serum A1AT (i.e., between 2-4 mg/mL, including 2.5 mg/mL) that patients should maintain to effect treatment. No surprising or unexpected results have been identified, but rather the proffered data appears to support a determination of obviousness because it merely confirms the expected and predicted results identified by the primary reference.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ratanatharathorn12 establishes the standard of care for prevention of grade II-IV acute GVHD is a treatment of tacrolimus and methotrexate (see, e.g., Ratanatharathorn at abs).
Nash200013 establishes that the combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse (see, e.g., Nash2000 at abs).
Nash199514 discusses the usage of tacrolimus in combination with methotrexate for the prevention of acute graft-versus host disease (see, e.g., Nash1995 at title, abs).
Przepiorka15 identifies that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation (see, e.g., id. at title, abs).
Rubio16 pertains to the impact of HLA matched and mismatched HCT (see id. at title, abs).
US 2009/0118162 A1 (Shapiro et al.; May 7, 2009 identifies that AAT was useful in the treatment and prevention of GvHD at least as early as 2006 (see, e.g., id. at claims 14-16 and 18).
US 20150104410 A1 (Eckelman et al; Apr. 16, 2015) discusses the state of the art circa 2015 regarding the use of AAT in the treatment of GvHD (see, e.g., US’410 at ¶[0134]) and identifies that AAT comprising peptides may be administered from about 0.1 mg/kg body weight to about 250 mg/kg body weight, with dosing frequencies that may range, for example, from twice daily to once a month (see, e.g., US’410 at ¶[0170]).
Petrache17 pertains to methods of treating patients by administering A1AT to patient to specifically “augment[] serum levels with intravenous infusions” of A1AT (see, e.g., Petrache at abs). Petrache identifies “[g]eneral treatment considerations” (see, e.g., id. at 195 at col I), and fairly informs artisans that it was known, circa 2009, that A1AT could be administered to patients routinely using biweekly, once weekly, “every two weeks”, and monthly treatments (see, e.g., Petrache et al. at 198-199 at bridging ¶), and by using dosages ranging from 60 mg/kg to at least 250 mg/kg (see, e.g., Petrache et al. at 198 at col II at final ¶ to 199 at col II at 1st full ¶). Petrache expressly informs artisans that, regarding A1AT therapy, “it is imperative to optimize” (see, e.g., Petrache et al. at 198 at col II at final ¶), and therefore the art identifies that, circa 2009, artisans understood that optimizing A1AT dosage and dosing frequency was “imperative” (id).
Giralt18 describes and explains “reduced intensity conditioning regimen” (see id., passim).
Gyurkocza19 identifies that “the conditioning regimen administered” before either an allogeneic or autologous hematopoietic cell transplantation (HCT), is an “essential component” of the HCT process because the conditioning regime is understood to “eliminate malignant disease” prior to reinfusion of the graft (see, e.g., Gyurkocza at title, abs). Gyurkocza explains that
Hematopoietic cell transplantation (HCT) is a potentially curative therapeutic approach for a variety of malignant and nonmalignant hematopoietic diseases. When HCT is performed in patients with malignant disorders, preparative or conditioning regimens are administered as part of the procedure to achieve 2 goals: provide sufficient immunoablation to prevent graft rejection and reduce the tumor burden.
(see, e.g., Gyurkocza at Introduction at 344).
Gyurkocza identifies that multiple conditioning regimes were known in the art (see, e.g., Gyurkocza at title, abs), including “reduced-intensity conditioning (RIC)” and “myeloablative, or ‘high-dose’ regimens” (see, e.g., Gyurkocza at 344 at col I-II at § Definitions). Each has different advantages and disadvantages recognized in the art, but myeloablative conditioning regimens are identified as having a benefit relative to RIC, namely lower relapse rates (see, e.g., Gyurkocza at 349 at col II at § Choice of conditioning regimens, 350 at 2nd full ¶).
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 WO 2017/117558 A1, Dinarello et al.; July 6, 2017; cited in IDS filed 11/20/2023 as Cite No. 6.
2 US 2009/0118162 A1; Shapiro et al.; May 7, 2009; cited in previous action.
3 WO 2017/117558 A1, Dinarello et al.; July 6, 2017; cited in IDS filed 11/20/2023 as Cite No. 6.
4 The rejection is revised as necessitated by Applicant amendment to address canceled and newly added claims. All cited portions and rationales supporting a determination of obviousness are maintained.
5 See, e.g., MPEP § 2144.05(I), noting 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.
6 See, e.g., MPEP § 2144.05(I), noting 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.
7 See, e.g., MPEP § 2144.05(I), noting 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.
8 See, e.g., MPEP § 2144.05(I), noting 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.
9 See, e.g., MPEP § 716.02(c)(II), explaining that evidence of expected beneficial results is evidence supporting a determination of obviousness.
10 MPEP §§ 716.05 and 716.07.
11 See also US 2009/0118162 A1 (Shapiro et al.; May 7, 2009; cited in previous action), which identifies that AAT was useful in the treatment and prevention of GvHD at least as early as 2006 (see, e.g., id. at claims 14-16 and 18).
12 Ratanatharathorn et al. (Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation, Blood, 92(7):2303-14 (Oct. 1, 1998); hereafter “Ratanatharathorn”; cited in IDS filed 11/20/2023 as Cite No. 26.)
13 Nash et al. (Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors, Blood, vol 96(6):2062-8 (2000 Sep 15); hereafter “Nash2000”; cited in IDS filed 11/20/2023 as cite No. 17).
14 Nash et al. (Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study, Blood, vol. 85(12):3746-53 (1995 Jun 15); hereafter “Nash1995”; cited in IDS filed 11/20/2023 as cite No. 18).
15 Przepiorka et al. (Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation, Blood, vol. 88(11):4383-9 (Dec. 1, 1996); hereafter “Przepiorka”; cited in IDS filed 11/20/2023 as cite No. 25)
16 Rubio et al. (The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party, Journal of Hematology & Oncology (2016) 9:65; hereafter “Rubio”; cited in IDS filed 11/20/2023 as Cite No. 29).
17 Petrache et al. (Safety and efficacy of alpha-I-antitrypsin augmentation therapy in the treatment of patients with alpha-I-antitrypsin deficiency, Biologics: Targets & Therapy, vol. 3:193-204 (2009); cited in IDS filed 11/20/2023 as cite No. 24; hereafter “Petrache”)
18 Giralt et al. (Reduced Intensity Conditioning Regimen Workshop-Defining the Dose Spectrum: Report of a Workshop Convened by the Center for International Blood and Marrow Transplant Research, Biol. Blood Marrow Transplant, vol. 15(3):367-369 (March 2009); hereafter “Giralt”; cited in IDS filed 11/20/2023 as cite No. 2).
19 Gyurkocza et al. (Conditioning regimens for hematopoietic cell transplantation: one size does not fit all, Blood, vol. 124(3):344-353 (July 17, 2014); hereafter “Gyurkocza”; cited in IDS filed 11/20/2023 as cite No. 4).
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