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 .
Applicant's election with traverse of group V, claims 9, 10, 13-16, and 19, and the species iron related inflammatory diseases and alveolar inflammatory responses in the reply filed on 10/1/25 is acknowledged. The traversal is on the ground(s) that the common inventive concept lies on the use of any antagonist of CD44/hyaluronic acid pathway for treating cytokine release syndrome. This is not found persuasive because each of the inhibitors have a different structure and act via different mechanisms. One cannot be substituted for another with expectation of identical activity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10, 14, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/1/25.
Improper Markush Rejection
Claims 9 and 16 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to delivery of antisense oligonucleotides or (shRNA/siRNA). Although each are nucleic acid inhibitory therapeutics, each of the categories have a different structure and act via different mechanisms.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific type of agent is dependent upon the specific structure and mechanism. There is no expectation that any one of the types of inhibitors as claimed can be substituted for any of the other with a completely different structure and mechanisms with the expectation of the same activity.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one type of inhibitory agent would not be evidence against any of the remaining members that have completely different structures and mechanisms and do not have identical activity.
Response to Arguments
Applicant argues that the inhibitors share a substantial structural feature, complementarity to CD44 mRNA-and a common property flowing from the feature—binding and inhibition translation to protein.
Contrary to applicant’s arguments, being any class of CD44 inhibitor that binds to CD44 mRNA is not sufficient to meet the criteria of a single structural similarity. Each of the inhibitors has a different structure and acts via a different mechanism. Certainly not every single possible type of complementary inhibitor could be examined in the same application. According to MPEP 2117, “Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention.” The instant agents are not functionally equivalent and would not be expected to have identical activity and behave in the same way. Each has a different structure and is processed differently intracellularly. Antisense oligonucleotides function by recruiting RNase H to cleave the RNA strand, preventing translation to protein. In contrast, siRNAs do not recruit RNase H, but instead bind to Argonaute proteins and function to guide those proteins to targets. Accordingly, siRNAs and antisense oligonucleotides s do not have sufficiently similar structures to provide the same function because each has a structure that dictates its pathway of action.
Claim Rejections - 35 USC § 112
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 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claim is directed to a method of treating cytokine release syndrome comprising administering any antisense oligonucleotide, shRNA, or siRNA targeting CD44, wherein the method is a method for the treatment of any iron related inflammatory diseases and/or alveolar inflammatory responses in a subject in need thereof.
The specification does not adequately describe which inflammatory diseases and alveolar inflammatory responses are related in any manner to iron.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being inflammatory diseases and alveolar inflammatory responses are related in any manner to iron.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for the instant diseases. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the as-filed application defines the term "Iron related inflammatory diseases" as having its general meaning in the art and referring to inflammatory diseases related to dysfunction in iron homeostasis (as-filed application, page 8, lines 1-2). The as-filed application further teaches the term "Iron related inflammatory diseases" relates to inflammatory diseases related to Iron Overload Syndromes and Iron related severe inflammatory response, particularly Iron related severe inflammatory response in COVID-19 patients (as-filed application, page 8, lines 2-6).
It is agreed that the specification discloses the terminology, but the specification does not adequately describe the criteria for the conditions to be included or excluded from the recited genus. One would not be able to readily envision which inflammatory diseases are “related” to dysfunction in iron homeostasis in any manner without further description of the genus of conditions that meet this criteria. The specification does not set forth what type of relationship is required.
Claims 9 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inhibition of CD44 via delivery of siRNA targeted to CD44 or for a method of decreasing iron in activated monocyte-derived M1 macrophages via delivery of siRNA targeted to CD44, does not reasonably provide enablement for a method for treatment of cytokine release syndrome via delivery of any antinsese oligonucleotide, shRNA, or siRNA targeting CD44 via any means; or for a method of treating any iron related inflammatory disease and/or alveolar inflammatory response. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement 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.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method for treatment of cytokine release syndrome via delivery via any means of any antisense oligonucleotide, shRNA, or siRNA that targets CD44.
The specification does not draw an adequate nexus between delivery of any antisense oligonucleotide, shRNA, or siRNA that targets CD44 at any position or any level of complementarity and the predictable outcome of treating cytokine release syndrome; or for the treatment of any iron related inflammatory disease and/or alveolar inflammatory responses.
The specification demonstrates that down-regulation of CD44 using a specific siRNA targeted to CD44 reduced the total amount of iron in activated monocyte-derived M1 macrophages compared to control RNA; and concludes that therefore CD44 mediates iron uptake during activation of inflammatory macrophages.
The specification discloses that the data “hints” towards a direct role of CD44-mediated iron endocytosis in the severe inflammatory response observed in SARS-CoV-2 patients (page 38), which is not commensurate in scope with the instant claims.
Inhibition of CD44 in cell culture via delivery of a specific CD44 siRNA with resultant reduction in the total amount of iron in activated monocyte-derived M1 macrophages is not commensurate in scope with treatment of any cytokine release syndrome via delivery of any agent within the instantly recited genus. The specification does not draw an adequate nexus between any level of inhibition of CD44 and the predictable outcome of treating any cytokine release syndrome. Additinoally, the claims encompass a large genus of agents that may not have any inhibitory activity on the target, as it is well known that targeting a specific transcript does not necessarily result in effective antisense oligonucleotides, shRNAs, or siRNAs.
Additionally, there is no guidance in the specification as filed that teaches how to deliver the instantly recited genus of antagonists, each having different delivery challenges, and predictably treat any cytokine release syndrome in vivo. Although applicant has demonstrated RNA interference in vitro via a specific CD44 siRNA, applicant is not enabled for mediating RNA interference in vivo by the broadly recited methods, as delivery is known in the art to be unpredictable with regards to dsRNA duplexes.
For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888). The instant claims are directed to a much broader genus of siRNAs or shRNAs that target CD44 but may not result in interference due to lack of specificity or poor selection of target location.
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art (a single species of the instant antagonists) for therapeutic in vivo applications. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating any cytokine release syndrome via broad systemic delivery of a broad genus of agents that act via different mechanism encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of each of the recited antagonists in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any cytokine release syndrome. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that the inventors have demonstrated for the very first time that, during activation of M1 macrophages, iron endocytosis is upregulated in a CD44-dependent manner and protein level of CD44 is increased. Additionally, the inventors have demonstrated the specific increase of lysosomal iron in M1 macrophages as the levels of the canonical iron endocytosis protein TfR1/CD71 remain unchanged (as-filed application, Figures 1 and 2). Moreover, the inventors showed that down-regulation of CD44 by a small interfering RNA (siRNA) targeting CD44 significantly reduced the total amount of iron in activated monocyte-derived M1 macrophages compared to a control RNA (as-filed application, Figures 3A and 3B). Given the physiopathological context of Cytokine Release Syndrome (CRS) and the well-established role of iron endocytosis, notably on the upregulation of genes involved in inflammation such as IL6R (see, e.g., Figure 2 of the as-filed application), these data not only support the role of CD44 in mediating iron uptake during inflammatory macrophage activation, but also indicate a direct role of CD44-mediated iron endocytosis in the severe inflammatory response characteristic of CRS.
Applicant is arguing limitations that are not claimed. The claims are directed to a method of treating any cytokine release syndrome via delivery of a broad genus of agents, wherein it would involve undue experimentation to determine which species of agents within the broadly recited genus would function by inhibiting CD44 and would predictably result in treating any cytokine release syndrome and treatment of any inflammatory disease with any relationship to iron and/or alveolar inflammatory responses. The claims are not limited decreasing CD44 with any specific agent that has demonstrated treatment of the instant scope of diseases.
The references cited by applicant are not enabling for a broad method of naked systemic delivery of any antisense oligonucleotide, shRNA, or siRNA targeting CD44 and the predictable outcome of treating any iron related inflammatory disease and/or alveolar inflammatory response. The claims are not directed to a method of decreasing iron accumulation via direct delivery of any specific agent. Applicant argues that it is clear that there is an undebatable link between the iron reduction in inflammatory macrophages and the treatment of Cytokine Release Syndrome. Further, the as-filed application demonstrates reduction in total amount of iron in activated monocyte-derived M1 macrophages by siRNA targeting CD44 (Example 2 and Figure 3) and, thus, enable one skilled in the art to practice the claimed method. However, the claims are not limited to a method of reduction in total amount of iron in activated monocyte-derived M1 macrophages by the siRNA targeting CD44 of the specification and to not demonstrate in vivo effects.
Applicant argues that the Supreme Court in Amgen v. Sanofi stated that "it may suffice to give an example (or a few examples) if the specification also discloses 'some general quality . . . running through' the class that gives it 'a peculiar fitness for the particular purpose."' Amgen Inc. v. Sanofi, 598 U.S. 594, 611 (2023). "In some cases, disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. Here, the as-filed application discloses the general quality of the claimed CD44 expression inhibitors-complementarity to CD44 mRNA to bind and block CD44 translation (as-filed application, page 18, lines 18-21, lines 28-32, and page 19, lines 3-7). This disclosed general quality gives CD44 expression inhibitors their peculiar fitness for the particular purpose of treating cytokine release syndrome when administered to a subject in need of treatment of cytokine release syndrome.
Contrary to applicant’s argument, in the instant case, it would involve undue experimentation to determine which specific inhibitors would in fact result in CD44 inhibition when delivered naked via any means; and it would involve undue experimentation to determine which specific disease states would be predictably treated via any level of inhibition of CD44 alone.
For example, Jordan et al. (Frontiers in Immunology, 2015, 6, 182, 1-14) teach that although CD44 has been targeted for therapy using specific siRNAs, a challenge with this approach is the alternatively spliced isoforms of CD44. Based on the sequence, the siRNAs may downregulate only certain CD44 variants. CD44 has multiple splice variants and isoforms with overlapping functions. Knocking down one isoform may not affect overall CD44 activity, especially if other isoforms compensate (page 8).
Jordan et al. teach: The presence of CD44 at high concentrations in the skin and other tissues and the necessity of HA pro duction for proper wound healing complicates potential clinical intervention strategies. Further understanding of the complexities of CD44 HA-dependent and independent signaling are required for developing highly specific targeted therapeutics that avoid the previously seen serious adverse reactions (page 10).
The instant specification is not enabling for the instant claim breadth.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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