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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/4/26 has been entered.
Applicant's election with traverse of group V, claims 9 and 16, 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Claims 10, 14, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
The opinion declarations by Stephanie Solier and Sebastian Muller are not convincing regarding the types of inhibitors simply belonging to antisense based technologies. It is general knowledge that each of the recited types of inhibitors are in the antisense based technology field, but each acts via a different mechanism and cannot be substituted one for the other with expectation of identical activity.
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.
Claims 9 and 16 are 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 cytokine release syndrome, 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.
Additionally, the specification does not adequately describe the structure required for the function for antisense oligonucleotides, shRNAs, and siRNAs that are targeted to CD44 and function as claimed. Certainly not any antisense oligonucleotide, shRNA, and siRNA that are targeted to CD44 will result in target inhibition.
For example, Bennett et al. (US 6,150,162) teach antisense modulation of CD44 expression and teach that various antisense oligonucleotides targeted to CD44 do not result in inhibition (see Table 1). Without further description of the structure required for the function, one would not be able to readily envision which antisense oligonucleotides, shRNAs, and siRNAs “targeting” CD44 would have the required function of treating cytokine release syndrome, iron related inflammatory diseases, or alveolar inflammatory responses. The specification does not adequately describe what specific structure or what level of complementarity is required for targeting to which region of what CD44 sequence to have the structure required for the function.
Additionally, the claims do not recite a specific CD44 nucleotide sequence by SEQ ID NO, but rather refer to the broad genus of CD44 sequences.
The claims encompass a method of introducing any antisense oligonucleotides, shRNA, or siRNA targeting any CD44 sequence, as well as encompass targeting any CD44 homolog or allele from any species known or yet to be discovered of CD44, as well as DNA genomic fragments, spliced variants or fragment that retains CD44-like activity.
Although the specification discloses a siRNA that is targeted to a specific CD44 sequence, the specification does not describe such agents directed to any other species of CD44 to describe the instantly claimed genus of any CD44. One of ordinary skill in the art could not make such agents to any CD44 without knowledge of the sequence. Given the breadth of sequences embraced in the instantly claimed genus, one could not envision the member agents that target such a broad genus.
Sahin et al. (Genes & Diseases (2020) 7, 205-216) teach: The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well (abstract).
Sahin et al. is evidence that for any given condition, the specific CD44 target isoform must be identified and delivery systems must be developed. The instant claims are directed to antisense oligonucleotides, shRNAs, and siRNAs targeting any CD44 isoform the treatment of cytokine release syndrome, any iron related inflammatory disease, or any alveolar inflammatory response.
Additionally, Sahin et al. (Expert Opin. Ther. Targets (2015) 19(12), 1587-1591) teach: CD44, a transmembrane proteoglycan known to be expressed in most human cancers and on cancer stem cells (CSC), has been investigated as a therapeutic drug delivery target via use either of its natural ligand, hyaluronic acid (HA), or via monoclonal antibodies (MAb) directed against the CD44 splice variant, v6. This is additional evidence that recitation of “CD44” is not directed to a specific target sequence.
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; and antisense oligonucleotides, shRNAs, and siRNAs that target CD44 and have the structure to function as claimed.
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 a CD44 antagonist inhibits demethylation of repressive histone marks H3K9me2 and H3K27me3, inhibits the depletion of H3K9me2 and inhibits the upregulation of iron-regulated genes such as IL6 receptor (as-filed application, page 10, lines 15-17). As demonstrated in the Examples, an inhibitor of CD44 expression as claimed, e.g., a CD44 siRNA, effectively reduces CD44 expression in activated M1 macrophages and substantially reduces the total amount of iron in activated M1 macrophages (as-filed application, page 38, lines 14-15, and Figure 3A). Applicant is arguing limitations that are not claimed. The claims are directed to a method for treatment of any cytokine release syndrome, and iron related inflammatory disease, or any alveolar inflammatory response, which is not commensurate in scope with inhibition of demethylation of repressive histone marks H3K9me2 and H3K27me3, inhibition of the depletion of H3K9me2 and inhibition of the upregulation of IL6 receptor.
Applicant argues that, as taught in the as-filed application, a reduction in iron levels in activated M1 macrophages by the CD44 inhibitors as claimed results in an inhibition of iron-regulated inflammatory mediators such as IL6 receptor and treatment of an iron-related inflammatory disease.
This statement by argument attempts to broaden the description of the specification from a reduction in iron levels in activated M1 macrophages (not claimed) to inhibition of iron-regulated inflammatory mediators other than IL6 receptor. Disclosure of a statement that the method can be used to treat an iron-related inflammatory disease is not an adequate description of what diseases are in fact included or excluded from the genus of iron-related inflammatory diseases.
Applicant argues that based on the teachings of the as-filed application, one skilled in the art readily recognized that Applicants were in possession of a method for the treatment of iron related diseases comprising administering a therapeutically effective amount of a CD44 expression inhibitor selected from an antisense oligonucleotide, shRNA, and siRNA targeting CD44. Contrary to applicant’s argument, one would not be able to readily recognize that applicant was in possession of a method for treating any disease related to iron in any manner (those that are caused by any up or down regulation of iron, for example) comprising administering a therapeutically effective amount of a CD44 expression inhibitor selected from any antisense oligonucleotide, any shRNA, and any siRNA targeting CD44, wherein it is known that not any of these agents targeted to CD44 inhibits CD44.
Applicant argues: Regarding alveolar inflammatory responses, the as-filed application teaches that inflammatory conditions related to dysfunction of alveolar macrophage function caused, e.g., by chest trauma, ischemia/reperfusion, hemorrhagic shock, and thermal burns, and more particularly conditions related to enhanced chemokine gene expression in alveolar macrophages, e.g., associated with Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), can be treated with a CD44 antagonist as claimed (as-filed application, page 4, lines 15-17, and page 8, lines 7-12).
Disclosure of a statement that the method can be used to treat alveolar inflammatory responses with a broad description of inflammatory conditions related to dysfunction of alveolar macrophage is not sufficient to allow one of ordinary skill to be able to readily envision the entire genus of specific conditions embraced by the instant claim language. The disclosure of the specification is not an adequate description of what diseases/conditions are in fact included or excluded from the genus of alveolar inflammatory responses.
Applicants argument regarding the role of alveolar macrophages (AMs) in the regulation of lung inflammation is not sufficient to allow one to readily envision which specific conditions are included in the instantly recited genus. As instantly drafted, the specific conditions are not evident.
Applicant argues that the existing knowledge in the field was that activated M1 macrophages enhance iron uptake and show increased proinflammatory cytokine expression and reduced anti-inflammatory cytokine expression (see, e.g., Cronin et al. Front. Mol. Biosci. 6:116, 2019, provided in a supplemental IDS, and Huang et al.). Thus, a skilled artisan recognized that a reduction in iron in activated M1 macrophages leading to reduced expression of inflammatory mediators was readily able to treat an iron-related inflammatory disease and/or an alveolar inflammatory response. Contrary to applicant’s arguments, it is unclear which specific inflammatory mediators are reduced via reduction in CD44 and which conditions are treated.
The species of inflammatory diseases associated with disturbed iron homeostasis as argued by applicant are not representative of the entire claimed genus. Contrary to applicant’s argument, the entire claimed genus of inflammatory diseases with any possible association to iron could not be readily be identified by one skilled in the art.
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 iron 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 specific siRNA of the specification targeted to CD44 or for a method of decreasing iron in activated monocyte-derived M1 macrophages via delivery of the specific siRNA targeted to CD44, does not reasonably provide enablement for a method for treatment of cytokine release syndrome via delivery of any antisense 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.
The instant specification does not draw an adequate nexus between reduction in iron levels in activated macrophages and the predictable treatment of cytokine release syndrome, any iron related inflammatory disease, or any alveolar inflammatory response.
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. Additionally, 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.
For example, Bennett et al. (US 6,150,162) teach antisense modulation of CD44 expression and teach that various antisense oligonucleotides targeted to CD44 do not result in inhibition (see Table 1).
The specification discloses in vitro cell culture of activated macrophages with specific CD44 siRNAs (SEQ ID NOs: 1-4) (Example 2) with a resultant downregulation of CD44 and reduction in the total amount of iron in activated macrophages compared to control. This is not commensurate in scope with the in vivo treatment via any means of delivery of any antisense oligonucleotide, shRNA, or siRNA targeting CD44 and the predicable outcome of the treatment of any cytokine release syndrome, the treatment of any iron related inflammatory disease, or the treatment of any alveolar response in a subject.
For example, Ganesh et al. (Biomaterials. 2013 April ; 34(13): 3489–3502) teach: targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery (abstract).
With regards to siRNAs, it was known that naked siRNA broadly delivered will not predictably reach the target tissue. The instant claims are not directed to any specific predictable carrier or mode of delivery.
Ganesh et al. teach: Naked siRNAs are unfavorable for systemic delivery because of their inherent limitations such as negative charge, large molecular weight, size, and instability. They are easily degraded by serum endonucleases and are quickly eliminated by renal excretion (page 2).
Singhai et al. (Genes & Diseases (2020) 7, 205-216) teach: The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well (abstract).
Sahin et al. is evidence that for any given condition, the specific CD44 target isoform must be identified and delivery systems must be developed. The instant claims are directed to antisense oligonucleotides, shRNAs, and siRNAs targeting any CD44 isoform the treatment of cytokine release syndrome, any iron related inflammatory disease, or any alveolar inflammatory response wherein the antisense oligonucleotides, shRNAs, and siRNAs are naked and can be delivered via any means.
Additionally, Sahin et al. (Expert Opin. Ther. Targets (2015) 19(12), 1587-1591) teach: CD44, a transmembrane proteoglycan known to be expressed in most human cancers and on cancer stem cells (CSC), has been investigated as a therapeutic drug delivery target via use either of its natural ligand, hyaluronic acid (HA), or via monoclonal antibodies (MAb) directed against the CD44 splice variant, v6.
This is additional evidence that recitation of “CD44” is not directed to a specific target sequence. The specification is not enabling for broad systemic delivery of any of the instantly recited agents targeted to any possible CD44 sequence and the predictable outcome of each of the instantly recited outcomes. Sahin et al. is also evidence of the challenges for CD44-targeted drug delivery (page 1590).
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).
Even in 2026, naked delivery of siRNA remains a challenge. For example, Longobardi et al. (Drug Delivery and Translational Research, 2026, 1-16) teach that efficient delivery of small interfering RNA (siRNA) remains a materials challenge because it requires nanocarriers that stabilize polyanionic cargo, support cellular interactions, and enable cytosolic delivery (abstract).
Longobardi et al. teach: Despite major clinical advances, efficient and selective small interfering RNA (siRNA) delivery remains a central materials challenge, with nanoparticle (NP) design playing a decisive role in overcoming extracellular and intracellular barriers (page 1).
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 Office Action has not provided a rationale why at the time of filing of the current application (2020) one skilled in the art would have to perform undue experimentation to design a siRNA targeting CD44, when at least since 2001 guidance on siRNA design was available. The Office Action has also not provided a rationale why one skilled in the art would have to perform undue experimentation to select CD44 as target gene, where the as-filed application teaches that CD44 siRNA reduces iron levels in activated M1 macrophages and the art, including Fujita, provides guidance on successfully delivering RNAi-based therapies even to hard-to-reach locations such as solid cancers.
Contrary to applicant’s arguments, the references cited by the examiner address issues that are still current in the siRNA art. For example, the need for the siRNA to have a certain level of complementarity to the target has not changed, as taught by Elbashir et al. Even in 2026, naked delivery of siRNA remains a challenge. For example, Longobardi et al. (Drug Delivery and Translational Research, 2026, 1-16) teach that efficient delivery of small interfering RNA (siRNA) remains a materials challenge because it requires nanocarriers that stabilize polyanionic cargo, support cellular interactions, and enable cytosolic delivery (abstract).
Longobardi et al. teach: Despite major clinical advances, efficient and selective small interfering RNA (siRNA) delivery remains a central materials challenge, with nanoparticle (NP) design playing a decisive role in overcoming extracellular and intracellular barriers (page 1).
As set forth above, it would involve undue experimentation to determine which specific CD44 is to be targeted by which specific inhibitory compound (specific sequence) that would result in the breadth of the instantly recited claims in a predictable manner. Applicant’s argument regarding the instant specification is not convincing because the siRNAs of the specification that target a specific region of a specific CD44 sequence and result in in vitro reduction of iron levels in activated M1 macrophages is not commensurate in scope with the instant claims which are not directed to reduction in iron levels in activated macrophages and encompass broad systemic delivery. The instant specification does not draw an adequate nexus between reduction in iron levels in activated macrophages and the predictable treatment of cytokine release syndrome, any iron related inflammatory disease, or any alveolar inflammatory response.
Regarding Jordan et al., which was cited in response to applicant’s arguments but is not a part of the rejection, applicant argues that Jordan et al. do not exclude the therapeutic use of CD44-targeting siRNA, and the Office Action's objection regarding CD44 isoforms appears to rest on an overgeneralization: nothing in Jordan et al. establishes that the existence of multiple isoforms would preclude one skilled in the art from designing CD44 siRNA or reasonably expect a therapeutically meaningful effect of CD44 siRNAs. Contrary to applicant’s arguments, the examiner did not assert that one of ordinary skill could not design CD44 siRNA, but rather that it would involve undue experimentation to determine which antisense oligonucleotides, shRNAs, or siRNAs with which sequences targeted to which CD44 isoform would predictably result in the instantly recited outcomes. 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).
Although applicant argues that it is not necessary to target all CD44 isoforms to achieve a significant reduction in iron accumulation, e.g., in activated macrophages, the specification is not enabling for broad naked systemic delivery of any of the instantly recited agents targeted to any of the CD44 isoforms alone with each of the instantly recited results in a predictable manner.
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)).
Applicant argues that the adverse effects discussed in Jordan et al. (allegedly disclosed at page 10 of this publication) relate specifically to anti-CD44 antibody-based targeting, resulting from antibody binding to CD44 as highly expressed on skin keratinocytes, which is not relevant to the pending claims, as the pending claims are not directed to such antibodies. Again, regardless of the inhibitory agent, the specification is not enabling for targeting any of the possible isoforms with each of the instantly recited outcomes in a predictable manner.
Applicant argues that with regard to a nexus between any level of inhibition of CD44 and the predictable outcome of treating any cytokine release syndrome (see Office Action, page 11), Applicants note that one skilled in the art was in possession of the knowledge on how to design, e.g., siRNAs that provide sufficient inhibition of CD44 expression and measure the sufficiency of inhibition, as exemplified in Applicants' examples where western blot analysis was used to quantify the effect of CD44 siRNA on CD44 protein expression in activated macrophages (see as-filed application, Figure 3B). Contrary to applicant’s arguments, it would certainly involve undue experimentation to determine which antisense oligonucleotides, shRNAs, and siRNAs targeted to any possible CD44 isoform from any species would result in a level of reduction that would predictably achieve each of the instantly recited outcomes.
Applicant argus that the as-filed application teaches that IL6 receptor, known to be involved in inflammatory diseases and responses, is one of the top iron-regulated genes and that an inhibitor of CD44 expression as claimed inhibits the upregulation of iron-regulated genes such as IL6 receptor (as-filed application, page 2, line 33 to page 3, line 1, and page 10, lines 15-17). This is not enabling for the instant method and is not enabling for inhibition of CD44 and any of the instantly recited outcomes. Involvement of IL6 in specific inflammatory diseases is not sufficient to enable the instant claim breadth and outcomes.
Applicant argues that it was known in the art (see Petzer et al.) that M1 macrophages are activated upon stimulation with IL6 (Petzer, page 2, second paragraph) and one skilled in the art would have reasonably expected that CD44 siRNA induced reduction in iron levels in M1 activated macrophages and consecutive reduction in IL6 receptor expression by said M1 macrophages would have reduced the activation status of such M1 macrophages and reduced their contribution to an inflammatory response. Applicant is arguing limitations that are not claimed.
Applicant draws their own nexus between what is actually exemplified in the specification, reduction in iron in activated M1 macrophages by a specific siRNA targeting CD44 of the specification that reduces IL6R expression and, thus, effects of the inflammatory cytokine IL6, among others, on M1 activated macrophages, would be expected by one skilled in the art to predictably treat an inflammatory condition such as a cytokine release syndrome, an iron-related inflammatory disease and an alveolar inflammatory response. However, this statement is not actual evidence of treatment of cytokine release syndrome via the instant claim breadth. The specification in fact does not demonstrate the treatment of cytokine release syndrome but rather makes an assumption that it may be treated via the disclosed CD44 inhibition,.
Applicant argues that consistent with this expectation, Petzer et al. teach that inflammation can be resolved by neutralizing inflammatory cytokines, e.g., using anti-IL6 receptor antibodies (Petzer et al., page 5, last paragraph). The basis of this argument is unclear because applicant argued that data from antibodies cannot be applied to the instant antisense oligonucleotides, shRNAs, or siRNAs. Additionally, the teaching of Petzer et al. is not commensurate in scope with the instant claims and is not enabling for a predictable method of treating each of the instantly recited categories of conditions.
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. 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 the specification does not demonstrate in vivo effects.
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 9 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (EP2102238A2), in view of Lee et al. (Blood, July 2014, VOLUME 124, NUMBER 2, pages 188-195) and Bennett et al. (US 6,150,162).
It is noted that the references are considered as enabled as the instant specification.
Xu et al. teach that the invention provides an anti- CD44 antibody that blocks cytokine production, and particularly cytokines such as TNF-α, IL-6 and IL-1 β (page 12).
Xu et al. does not teach a method for the treatment of cytokine release syndrome comprising administering an antisense oligonucleotide (first recited species), siRNA, or shRNA targeting CD44.
However, it would have been obvious to treat cytokine release syndrome comprising administering an inhibitor of CD44 because Lee et al. teach that cytokine release syndrome is associated with elevated circulating Introduction levels of several cytokines including interleukin (IL)-6 and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. Since Xu et al. teach that inhibition of CD44 inhibits IL-6 and Lee et al. teaches that inhibition of IL-6 treats cytokine release syndrome, it would have been obvious with a reasonable expectation of success to inhibit CD44 to inhibit IL-6 and treat cytokine release syndrome.
IT would have been obvious to utilize an antisense oligonucleotide as the inhibitor as a matter of design choice because Bennett et al. teach antisense modulation of CD44 expression and teach that various antisense oligonucleotides targeted to CD44 result in effective target inhibition (see Table 1) (instant claim 9).
Instant claim 16 recites an additional outcome of the method rather than an additional method step and therefore it would necessarily flow from the recited method step of the base claim, delivery of the inhibitor of CD44 to treat cytokine release syndrome.
Conclusion
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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