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 .
Priority
The present Application, filed December 15, 2022, is a Continuation-In-Part of International Patent Application No. PCT/EP2022/051940, filed January 27, 2022. The present Application also claims priority to International Patent Application PCT/IB2021/000033, filed January 28, 2021, and to European Patent Application No. EP21199256, filed September 27, 2021.
Status of the Claims
In the amendment filed March 17, 2023, claims 1-152 are canceled and new claims 153-177 are added. Claims 153-177 are currently pending.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 20, 2023, May 14, 2024, June 24, 2024, March 12, 2025, April 23, 2025, and August 7, 2025 are acknowledged.
Claim Objections
Claim 169 is objected to because of the following informalities: the claim recites “an amount sufficient to reduce…and/or delaying.” The syntax of “delaying” appears to be incorrect, and should be “delay.” Appropriate correction is required. It is also noted that the form of the abbreviation is slightly different in different claims. Claim 171 recites “GvHD” (lowercase v) whereas claims 168, 170, and 174 recite “GVHD” (capital v). This usage should be made uniform.
Claim Rejections - 35 USC§ 112(a) - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 161 is rejected for failure to satisfy the enablement requirement:
Claim 161 is rejected under 35 U.S.C. § 112(a), as failing to comply with the enablement requirement. The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The standard for determining whether the specification meets the enablement test was first stated in Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916), and asks if the experimentation needed to practice the invention is undue or unreasonable. The claimed invention is enabled if any person skilled in the art can make and use the invention without undue experimentation. The focus is on 'undue' rather than on ‘experimentation’ (In re Wands, at 737, 8 USPQ2d at 1404; see also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988)). A patent need not teach what is well known in the art (In re Buchner, 929 F.2d 660, at 661, 18 USPQ2d 1331, at 1332 (Fed. Cir. 1991); Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384, at 231 USPQ 81, at 94 (Fed. Cir. 1986), cert. denied, 480 U.S. 947 (1987); Lindemann Maschinenfabrik GMBH v. American Hoist & Derrick Co., 730 F.2d 1452, at 1463, 221 USPQ 481, at 489 (Fed. Cir. 1984)). Determining whether claims are sufficiently enabled by the specification is based on underlying findings of fact. In re Vaeck, 947 F.2d 488, at 495, 20 USPQ2d 1438, at 1444 (Fed. Cir. 1991); Atlas Powder Co. v. E.l du Pont de Nemours & Co., 750 F.2d 1569, at 576, 224 USPQ 409, at 413 (Fed. Cir. 1984).
The Breadth of the Claims
Claim 161 is potentially substantially broad, as it encompasses every composition of claim 153 that satisfies the functional condition of being “stable” for at least 24 months at 25 °C. Claim 153, from which claim 161 depends, recites a genus of pharmaceutical formulations having mocravimod, or a derivative thereof, in combination with four or five different excipients. Because the amounts of these excipients, as well as the processing parameters for preparing the formulation, are unspecified, the range of possible formulations of claim 153 is very large. It is unknown what proportion of these formulations would satisfy the functional limitation of claim 161, due to the absence of examples and the unpredictability of the art as discussed below, but this proportion could potentially encompass a large range of formulations as well.
The Nature of the Invention, and the Level of One of Ordinary Skill
The art is somewhat multidisciplinary, involving formulations science as well as analytical chemistry and quality testing/quality control principles. The claimed invention requires skill in formulation design and preparation, stability testing, and reliability with HPLC and appropriate selection and operation of detection methods. Where the specification fails to provide guidance, the person of ordinary skill in the art would be capable of identifying the appropriate art for the requisite guidance. Accordingly, those of ordinary skill in the art would understand that certain amounts of experimentation will be required. For example, as it relates to Applicants' claimed invention, one of ordinary skill in the art would almost certainly find that considerable experimentation is necessary in preparing a large number of formulations of claim 153 as candidates for the stability criterion of claim 161. Furthermore, one would likely find that experimentation is necessary to develop HPLC separation and detection procedure suitable for the different formulations, enabling reliable detection of a fraction of a percent of impurities.
The Amount of Guidance, and the Existence of Working Examples
Claim 153 provides the general outline of the composition of the formulations of claim 161, and one preparing these formulations would operate within that framework. It is unclear whether the specification provides a single example of a formulation that satisfies the stability criterion of claim 161. At pg. 23, lines 12-14, the specification describes a “preferred stable formulation of the present disclosure,” but because multiple definitions of stable are provided, including having less than 0.7% impurity after 1 month of storage (pg. 23, lines 20-21), it is unclear whether this example meets the two year stability criterion of claim 161. As such, the person preparing the candidate formulations would have minimal guidance on narrowing the composition from the broad outlines of claim 153, and would of necessity need to prepare a vast number of formulations of varying component percentages and possibly preparation procedures to merely explore the landscape of possibly sufficiently stable formulations.
At pg. 24, lines 1-4, the specification generally describes a procedure for testing the stability via HPLC, in this case at the end of two years’ storage. While the disclosed procedure does not specify a detection method, which would be a significant variable, one of skill in the art would be able to select an appropriate detection method, such as mass spectrometry. Sufficient separation methods would likely need to be developed.
The State of the Prior Art and the Level of Predictability in the Art
The art of formulation stability is substantially unpredictable.
The non-patent publication, The Role of Solid State Characterization in Predicting Stability of Solid Dosage Forms, Curr. Pharm. Des., 22, pgs. 5109-5028 (2016) by Szabo et al. (hereinafter, “Szabo”) teaches that solid drug formulation stability is a complex and unpredictable art:
"Stability is a very complex feature and is influenced not only by the stability of the drug substance but also by the stability of excipients and the interaction of the components within the system. Another important contributing factor is the packaging material, which is responsible for the protection of the drug product. Not only drug substances, but also excipients are susceptible to different degradation mechanisms."
-Szabo, at page 5109, Abstract.
Similarly, the non-patent publication, Impact of excipient interactions on solid dosage form stability, Pharm Res., 10, pgs. 2660-2683 (2012) by Narang et al. (hereinafter, “Narang”) states that:
" Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities…. special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways."
-Narang, at page 2660, Abstract.
Similarly, the non-patent publication, Excipient Stability in Oral Solid Dosage Forms: A Review, AAPS Pharm Scitech., 19, pgs. 12-16 (2018) by Darji et al. (hereinafter, “Darji”) states that the amount of a given excipient can alter stability as well as on impurities in the excipient:
"The oxidation [of a particular API] was observed to depend on the impurities present in the pharmaceutical excipients used in the formulation. Further, a mechanism involving Schiff base formation, double bond isomerization, and subsequent hydrolysis was proposed to account for the formation of the degradant, and the extent of its formation was observed to be influenced by the amount of mannitol used as an excipient in the formulation."
-Darji, at page 22, left column, fourth full paragraph
Darji further describes that the amount of impurities in an excipient will frequently vary from batch-to-batch, further complicating the situation:
"The chemical impurities of magnesium stearate include magnesium oxide (MgO), palmitic acid, and magnesium palmitate. The amount of impurity varies between batches, thus leading to variation in the physical properties of magnesium stearate."
-Darji, at page 16, left column, Lubricants, Anti-Adherents, and Glidants
In short, it is consistently observed that the art of formulation stability is highly unpredictable, with stability being influenced by a variety of factors, including some (such as impurities in the starting material, batch variation, humidity, storage vessel) that are not accounted for in the recitation of claim 161.
The Quantity of Experimentation
As described above, the experimentation required simply to evaluate the landscape of claim 161 would involve the preparation and testing of a very large number of individual formulations within the scope of claim 153, to gain a rough idea what types, if any, are within the scope of claim 161. This would potentially also require repeating experiments of individual formulation, and varying parameters such as excipient source and batch. Furthermore, due to the nature of the functional limitation of claim 161 (stability after two years of storage), the time from preparing the formulation to determining whether it satisfies the limitation of claim 161 would be two years. As such, the required experimentation would not only be great in scope, but also considerable in the time required.
Accordingly, in order to enable the invention as claimed, one of ordinary skill in the art would have to resort to undue experimentation.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 157 fails to further limit the subject matter of its base claim:
Claim 157 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 157 recites wherein the solid dosage form is immediate or modified release such as delayed. By definition, any composition that releases an API must be either immediate release or delayed release. Because claim 157 includes all possible categories, in terms of relative release rate, it fails to further modify the base claim, claim 153, from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 164-165 and 168 are anticipated by Zon:
Claims 164-165 and 168 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. Patent No. 9,763,9880 to Zon et al. (hereinafter, “Zon”).
Claim 164 recites a method of treating a hematological malignancy, e.g., acute myeloid leukemia (AML), in a subject undergoing allogeneic hematopoietic stem cell transplant (HSCT), wherein the method comprises administering to the subject a therapeutically effective amount of an S1P receptor modulator. The additional optional limitation, because it is not required, is not considered here for anticipation purposes.
Zon teaches, inter alia, the use of a CXCR4 antagonist in concert with an S1P receptor modulator to promote HSC (hematopoietic stem cell) engraftment in a recipient subject of a HSC transplant (Abstract). To this end, Zon teaches that the combination of a CXCR4 antagonist and at least one S1P receptor modulator can be of use in treating subjects suffering from hyperproliferative disorders of the hematopoietic system, such as chronic or acute myelogenous leukemia (col. 9, lines 39-46). Zon specifies that this method (involving co-administration of a CXCR4 antagonist and at least one S1P receptor modulator) can yield improved outcomes both via improved stem cell mobilization when administered to a donor of a hematopoietic stem cell transplantation (HSCT), or via improved engraftment when administered to a recipient of a HSCT (col. 9, lines 10-14).
As such, Zon discloses a method of treating a hematological malignancy (such as acute myelogenous leukemia) in a subject undergoing allogeneic hematopoietic stem cell transplant – i.e. a HSCT recipient), wherein the method comprises administering to the subject a therapeutically effective amount of an S1P receptor modulator (in this case, in conjunction with a CXCR4 antagonist). Claim 164 is therefore anticipated.
With respect to claim 165, Zon teaches that in some embodiments, a S1P receptor modulator agent suitable for use in the disclosed method is FTY720 (fingolimod – col. 42, lines 18-49). With respect to claim 168, the CXCR4 antagonist of Zon that is administered with the S1P receptor modulator is a chemotherapeutic agent; and Zon teaches administering this chemotherapeutic agent to a subject in need of HSCT (col. 5, lines 35-42), and thus its administration constitutes the conditioning step. Zon teaches that this pretreatment can allow transplantation to proceed in patients who would not otherwise be considered candidates for HSCT, and thus treats performing an allogeneic transplantation of HSCs into the subject, after the conditioning step.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 153-158 and 160-163 are obvious over Kojima and Liu:
Claims 153-158 and 160-163 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S Patent No. 8,318,881 to Kojima et al. (hereinafter, “Kojima”), in view of U.S. Patent No. 9,925,138 to Liu (hereinafter, “Liu”).
Claim 153 recites a pharmaceutical composition comprising (i) an S1P receptor modulator of formula (II) or a phosphorylated variant thereof:
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(ii) sodium starch glycolate, (iii) magnesium stearate, (iv) colloidal silicon dioxide, and ((v) at least one compound selected from mannitol, microcrystalline cellulose, and a mixture thereof. The compound of formula (II) is referred to hereinafter as mocravimod.
Kojima teaches a series of closely related compounds for the treatment of inflammatory bowel disease and having chemical formula 1 (Abstract)
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Kojima teaches these compounds are sphingosine-1-phosphate receptor agonists (col. 1, lines 9-12). In a real example, Kojima teaches 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol and hydrochloride salts thereof (col. 6, lines 6-9 and 43-47). This compound, referred to as KRP-203 in Kojima, is mocravimod. Kojima further teaches a mocravimod capsule, prepared by blending ~0.04% mocravimod, ~99% mannitol, and ~1% magnesium stearate, and packaging the resulting powder blend in a capsule (all percentages are w/w). Kojima thus teaches a pharmaceutical composition having an S1P receptor modulator of formula (II), magnesium stearate, and mannitol, but does not expressly teach that the composition includes sodium starch glycolate or colloidal silicon dioxide. It would have been obvious to incorporate these components into the composition of Kojima, however, because these were well-known in the art as conventional excipients for solid pharmaceutical formulations of S1P receptor agonists. See, for example, Liu.
Liu teaches pharmaceutical dosage forms (pharmaceutical compositions) containing fingolimod (Abstract), which is a S1P receptor agonist (col. 2, lines 10-24):
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Liu teaches and also teaches the compositions produced by the disclosed methods. Liu teaches the composition can include one or more sugar alcohols, such as mannitol (col. 10, lines 4-15); and may further include conventional pharmaceutically acceptable excipients such as lubricants, fillers, binders, disintegrants, and glidants (col. 10, lines 65 through col. 11, line 1). An exemplary suitable lubricant is magnesium stearate (col. 11, lines 8-10), an exemplary suitable disintegrant is sodium starch glycolate (col. 12, lines 17-20), and an exemplary suitable glidant is colloidal silicon dioxide (col. 12, lines 25-27). It would have been obvious to incorporate the conventional disintegrant, sodium starch glycolate, and the conventional glidant, colloidal silicon dioxide, as taught for the stable S1P receptor agonist pharmaceutical composition of Liu, into the mocravimod pharmaceutical composition of Kojima.
With respect to claim 154, Kojima teaches that the composition can have a pharmaceutically acceptable salt of mocravimod (Abstract), such as a hydrochloride salt (e.g. col. 6, lines 1-3). With respect to claim 155, Liu teaches an exemplary suitable filler for the pharmaceutical composition is microcrystalline cellulose (col. 11, lines 19-21). It thus would have been obvious to utilize a combination of microcrystalline cellulose, as taught by Liu, and mannitol, as taught by both Kojima and Liu. With respect to claim 156, as noted, the real example of Kojima is in the form of a capsule (col. 9, lines 1-17). Because, as noted above, claim 157 fails to further limit the base claim from which it depends, claim 157 is obvious for the same reason as is claim 153.
With respect to claim 158, Kojima teaches that the capsule contains 0.1 mg of mocravimod (KRP-203; col. 9, lines 5-13). With respect to claim 160, Liu teaches that in some embodiments, the fingolimod should be micronized and exhibit a mean particle size less than 25 microns. While this is not identical to the less than 8 µm of instant claim 160, it substantially overlaps, and 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 (CCPA 1976).
With respect to claims 162-163, claim 162 recites a process of preparing the pharmaceutical composition of claim 153, wherein the process comprises adding and blending the components discussed above in a particular order. As discussed, Kojima, as modified by Liu, discloses a process of preparing a capsule, comprising adding and blending the components of S1P receptor modulator, microcrystalline cellulose, colloidal silicon dioxide, mannitol, sodium starch glycolate, and magnesium stearate, and then collecting (recovering) the blend, filling a capsule with it, and possessing (recovering) the filled capsule. Neither Kojima nor Liu discloses the precise sequence of adding and blending the components as recited in claim 162 (and by extension, claim 163), but selection of an order of mixing ingredients is prima facie obvious, particularly in the absence of any showing of new or unexpected results, or any particular benefit to the recited order. In re Gibson 39 F.2d 975 (CCPA 1930); see also MPEP 2144.04(IV)C. In the instant case, no evidence of unexpected results or any particular benefit to the recited order is shown, and so the order of addition and mixing of the formulation ingredients is prima facie obvious.
Claim 159 is obvious over Kojima, Liu, and Legangneux:
Claim 159 is rejected under 35 U.S.C. § 103 as being unpatentable over Kojima, in view of Liu, further in view of U.S. Patent Application Publication No. 2017/0027907 to Legangneux et al. (hereinafter, “Legangneux”).
With respect to claim 159, Liu teaches ~200 mg tablets (e.g. Examples 1, 2, 7, and 8) and teaches that the tablets can have 20-95% sugar alcohol (e.g. ~40-190 mg mannitol, col. 10, lines 45-48), 0.5 to 5 wt% lubricant (e.g. 1-10% magnesium stearate, col. 11, lines 14-18); (0-20% filler (e.g. 0-40 mg microcrystalline cellulose). With respect to disintegrants and glidants, Liu does not expressly state amount ranges, but states that the amount of these (and all) excipients present in the solid dosage forms will vary depending upon the specific and desired properties of the solid dosage form, and that ranges and amounts of these excipients are known and reported in the literature (col. 11, lines 3-7). It would have been obvious to utilize amounts of filler (e.g. microcrystalline cellulose) and glidant (e.g. colloidal silicon dioxide) in amounts within the recited ranges, because these amounts were known in the art as suitable for pharmaceutical compositions, see, for example, Legangneux.
Legangneux teaches formulations of the S1P receptor modulator, Siponimod (Abstract), that can include excipients such as a dis and a glidant. Legangneux teaches the glidant can be present at 1-3 wt% (paragraph [00553]) and the disintegrant can be present 2-8 wt% (paragraph [0055]). In the capsule or tablet of Kojima and Liu, this would correspond to 2-6 mg of colloidal silicon dioxide and 4-16 mg of sodium starch glycolate. These amount ranges are not identical to the ranges recited in instant claim 159, but substantially overlap with them, and 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 (CCPA 1976).
Claims 166-167 and 169 are obvious over Zon and Smith:
Claims 166-167 and 169 are rejected under 35 U.S.C. § 103 as being unpatentable over Zon, in view of the non-patent publication, Sphingosine 1-Phosphate Signaling and Its Pharmacological Modulation in Allogeneic Hematopoietic Stem Cell Transplantation, Int. J. Mol. Sci., 18, pgs. 1-12 (2017) by Smith et al. (hereinafter, “Smith”).
Claim 166 recites the method of claim 164 wherein the S1P receptor modulator is mocravimod or one of several other species, while claim 167 recites wherein the S1P receptor modulator is mocravimod. Claim 169 recites the method of claim 164 wherein the S1P receptor modulator is mocravimod, with an optional limitation that is not considered applied here because it is not required. Zon is applied to these claims as to claim 164 above, but does not expressly teach mocravimod as an exemplary suitable S1P receptor modulator. It would have been obvious to one of ordinary skill in the art that mocravimod could be used as the S1P receptor modulator with a reasonable expectation of success, for example in place of the fingolimod described above, because mocravimod was known in the art as an S1P receptor modulator and to be substantially functionally similar to fingolimod. See, for example, Smith.
Smith is a review that discusses, inter alia, different means by which S1P receptor modulators can attenuate inflammatory diseases (Abstract). Smith discloses that fingolimod has been approved for clinical use and, when converted to the active form in vivo by phosphorylation, binds to 4 of the 5 S1P receptors. Smith further discloses that KRP203 (mocravimod) is a newer generation S1P receptor modulator designed to be more selective to S1P receptor 1 (pg. 2, Sphingosine 1-Phosphate (S1P) and the S1P Receptors (S1PRs)) and has the same underlying mechanism of action as fingolimod (pg. 2, Pharmacological S1PR Modulation). On this basis, it would have been obvious to utilize the mocravimod of Smith in the method of Zon, in place of the fingolimod of Zon, and one would have had a reasonable expectation of success in doing so, based on the identical underlying mechanism of action. On this basis, claims 166-167 and 169 are obvious.
Claim 170 is obvious over Zon and Ruegger:
Claim 170 is rejected under 35 U.S.C. § 103 as being unpatentable over Zon, in view of U.S. Patent No. 8,673,918 to Ruegger et al. (hereinafter, “Ruegger”).
Claim 170 recites the method of claim 164, wherein said S1P receptor modulator is administered in an amount sufficient to reduce the risk of chronic GVHD and/or delay chronic GVHD onset. Zon is applied to claim 170 as to claim 164 above, but does not expressly disclose administering the S1P receptor modulator in an amount sufficient to achieve this result. It would have been obvious, however, to administer the S1P receptor modulator in an amount sufficient to reduce the risk of chronic GVHD occurrence because it was known in the art that S1P receptor modulators can be effective to prevent graft-versus-host disease. See, for example, Ruegger.
Ruegger teaches stable compositions comprising a S1P receptor modulator, suitable for use as a dosage form (Abstract), including preferred embodiments where the S1P receptor modulator is the fingolimod of Zon (i.e. FTY720, Ruegger col. 9, lines 20-30). Ruegger further teaches that the compositions can be useful for preventing graft-versus-host disease such as sometimes occurs following bone marrow transplantation. It would have been useful to adapt such GvHD prevention to the method of Zon by administering the fingolimod in a dosage form of Ruegger sufficient to prevent (reduce the risk of) chronic GvHD occurrence.
Claims 171-173 and 175-177 are obvious over Corrado and Smith:
Claims 171-173 and 175-177 are rejected under 35 U.S.C. § 103 as being unpatentable over Taiwanese Patent Application No. TW202011948 to Corrado et al. (hereinafter, “Corrado”), in view of Smith. A machine translation of Corrado, along with the related U.S. Patent Application Publication No. 2021/0283073, are attached to this action. Note that the content of US20210283073A is not identical to that of Corrado and, in particular, paragraph numbers generally do not match. Paragraph numbers cited below are those of Corrado.
Claim 171 recites a method of preventing or treating chronic GvHD (graft-versus-host disease) in a subject undergoing allogeneic hematopoietic stem cell transplant (HSCT), wherein the method comprises administering to the subject a therapeutically effective amount of an S1P receptor modulator. As a matter of claim interpretation, it is noted that the preambular recitation of treating chronic GvHD is afforded patentable weight to the extent that it dictates subject selection (i.e. selecting subject who are experiencing GvHD after receiving a HSCT). However, the preambular recitation of preventing chronic GvHD is regarded as a mere intended result that is not entitled to patentable weight, as it does not distinguish the method from methods of administering a S1P receptor modulator to a HSCT patient for any other intended purpose (such as improving engraftment as taught by Zon).
Furthermore, the term “undergoing” as in “a subject undergoing HSCT” does not appear to clearly imply any chronology, and so the method of claim 171 is understood as generally including methods involving S1P receptor modulator administration before, during, or after HSCT, although in the case of treating (an already extant case of) GvHD, administration would presumably only occur after the transplantation.
Corrado teaches a method for improving patient survival, the method comprising administering 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol (mocravimod) or a pharmaceutically acceptable salt thereof to patients undergoing hematopoietic stem cell transplantation for the treatment of hematological malignancies (claim 16, paragraph [0007]). Corrado does not expressly state that this method is applied to specifically to patients experiencing or at particular risk of GvHD, for the particular purpose of treating GvHD, however it would have been obvious to utilize mocravimod for this specific purpose, because it was known in the art that S1P modulation had the potential by regulating GvHD. See, for example, Smith.
Smith, beyond what is noted above, is a review that discloses that pharmacological invention via S1P modulation may have the potential to improve patient outcome by regulating GvHD (Abstract). Smith teaches that binding of agonistic compounds such as KRP203 (mocravimod) to the S1P receptor-1 (S1PR1) subtype on T lymphocytes results in internalization of the S1PR1 rendering the T cells unresponsive to egress signal from the S1P; and via this mechanism the attenuation of inflammatory diseases has mainly been attributed to the functional antagonistic effects of S1PR agonists at the S1PR1 subtype (pg. 2, Pharmacological S1PR Modulation). Smith concludes that such finding suggest that functional antagonism of S1PR1 (e.g. by S1PR agonists like mocravimod) has the potential to improve patient outcome by regulating GvH disease (pg. 7, Conclusions). It thus would have been obvious to apply the method of Corrado explicitly to patients undergoing HSCT and at risk of or experiencing GvHD, for the purpose of preventing or treating the GvHD.
With respect to claims 172 and 173, Corrado teaches that the patient is suffering from hematological malignancy, such as acute myeloid leukemia (claim 19, paragraph [0007]). With respect to claim 174, Corrado teaches that administration of mocravimod can begin before HSCT and resume after HSCT (paragraph [0019]) and that the HSCT can be co administered with a chemotherapeutic such as cyclosporin A (paragraph [0020]). Such administration of cyclosporin A prior to HSCT would thus constitute a conditioning step of claim 174, that is followed by the transplantation step of claim 174.
With respect to claims 175, 176, and 177, as noted Corrado teaches the S1P receptor modulator is mocravimod (e.g. claim 16) and Smith suggests mocravimod would be a useful agent as well (pg. 2, Pharmacological S1PR Modulation).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 164-177 are rejected for nonstatutory double patenting over the ’588 application, Zon, Corrado, Smith, and Ruegger:
Claims 164-177 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, and 7-11 of U.S. Patent No. 18/869,588 (hereinafter, “the ’588 application”), in view of Zon, Corrado, Smith, and Ruegger. This corresponds to U.S. Patent Application Publication No. 2025/0213503, which is cited in the form 892 attached to this action. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the ’588 application recite similar methods involving administration of a S1P receptor modulator in conjunction with a CAR cell composition, and thereby overlap substantially with the subject claims. For example, claim 1 of the ’588 application recites a method for treating a hematological cancer in a subject in need thereof, comprising administering an effective amount of a S1P receptor agonist in said subject, wherein said S1P receptor agonist is Mocravimod or a derivative thereof. As such, it encompasses instant claim 164. Claim 1 of the ’588 application, as modified by Corrado and Smith, similarly encompasses instant claim 171. Zon, Corrado, Smith, and Ruegger are applied to claims 165-177 as above.
Claims 164-177 are rejected for nonstatutory double patenting over the ’272 application, Zon, Corrado, Smith, and Ruegger:
Claims 164-177 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 18/839,272 (hereinafter, “the ’272 application”), in view of Zon, Corrado, Smith, and Ruegger. This corresponds to U.S. Patent Application Publication No. 2025/0170176, which is cited in the form 892 attached to this action. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the ’272 application recite similar methods involving administration of a S1P receptor modulator in conjunction with a CAR cell composition, and thereby overlap substantially with the subject claims. For example, claim 1 of the ’272 application encompasses instant claim 164. Claim 1 of the ’272 application, as modified by Corrado and Smith, similarly encompasses instant claim 164. Zon, Corrado, Smith, and Ruegger are applied to claims 165-177 as above.
Conclusion
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629