DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Amendments to the Specification, Amendments to the Claims and Arguments/Remarks filed 09 July 2026, in response to the Office Correspondence dated 18 May 2026, are acknowledged.
The listing of Claims filed 09 July 2026, have been examined. Claims 1, 5-7, and 9-11 are pending. Claims 2-4, 8, 12-16 are canceled and claims 1 and 9 are amended.
Response to Amendment
The amendments to claims 1 and 9, and the cancellation of claims 2‑4, 8, and 12‑16, have been entered.
The applicant has amended independent claim 1 to limit the recited TPM1 inhibitor to one of three specifically identified small interfering RNA (siRNA) molecules corresponding to SEQ ID NOS: 17-22 as disclosed in Example 2 of the originally-filed specification. The applicant has also removed the previously-recited TREM2 silencer limitation that formed the basis for several of the prior rejections. Dependent claim 9 has likewise been amended to depend from claim 7 and to recite that the administration form "is" selected from a recited list of delivery forms rather than using the previously-recited transitional language. The amendments have been carefully considered.
The amendment to claim 1 substantially narrows the scope of the claims by limiting the TPM1 inhibitor to specifically identified synthetic siRNA species. Consequently, the prior rejections under 35 U.S.C. §112(a) directed to the absence of written description and enablement for a generic TPM1 inhibitor encompassing TREM2 silencers are no longer applicable to the claims in their present form to the extent those rejections relied upon the breadth of the previously-recited TPM1 inhibitor/TREM2 silencer genus. Likewise, the amendment removing the TREM2 silencer limitation overcomes the prior indefiniteness rejection based upon the internally inconsistent recitation that a TPM1 inhibitor "comprises a TREM2 silencer." The ambiguity identified in the previous Office Correspondence no longer exists because the claims now positively recite specific TPM1-targeting siRNA species.
The amendment to claim 9 placing the claim in proper dependency from claim 7 also overcomes the previous rejection under 35 U.S.C. §112(d), since claim 9 now further limits the administration form recited in claim 7 rather than creating ambiguity regarding the claim from which it depends. The applicant has additionally corrected the sequence listing incorporation-by-reference statement to identify the XML file size in bytes rather than kilobytes. This correction satisfies the previously-made objection under 37 CFR 1.835(a)(2).
Accordingly, the following prior rejections are withdrawn: the rejection under 35 U.S.C. §112(a) based upon lack of written description directed to the previously-recited TPM1 inhibitor comprising a TREM2 silencer; the rejection under 35 U.S.C. §112(a) based upon lack of enablement directed to the previously-recited TPM1 inhibitor comprising a TREM2 silencer; the rejection under 35 U.S.C. §112(b) directed to the ambiguity created by the TPM1 inhibitor/TREM2 silencer limitation; the rejection under 35 U.S.C. §112(d) directed to improper dependency of claim 9; and the objection concerning the Sequence Listing XML incorporation-by-reference statement.
The amendment to claim 1 substantially changes the character of the claimed invention. Unlike the previously-recited generic TPM1 inhibitor, amended claim 1 positively recites three specifically identified synthetic siRNA molecules having defined nucleotide sequences. The claimed siRNAs are not naturally occurring molecules isolated from nature, but rather are synthetic oligonucleotides intentionally designed to produce sequence-specific RNA interference. The claims therefore no longer merely recite a natural law or naturally occurring biological relationship. Accordingly, the previous rejection under 35 U.S.C. §101 is persuasive no longer. The rejection under 35 U.S.C. §101 is therefore withdrawn.
The amendments materially change the obviousness analysis. The original 35 U.S.C. §103 rejection findings were directed to a broader claim scope than now presented. The independent claim is now limited to three specific TPM1-targeting siRNA species (SEQ ID NOS. 17-22) rather than a broad functional genus. Consequently, the prior 35 U.S.C. §103 rejections are withdrawn and new 35 U.S.C. §103 rejections, necessitated by amendment to the claims, have been entered as detailed below.
The new rejections establish that the particular claimed sequence-specific TPM1 inhibitor siRNA species would have been obvious to select to one of ordinary skill in the art, with a reasonable expectation of success, after identification of TPM1 as a validated therapeutic target for retinal degeneration. The new rejections expressly address why the now specifically-recited siRNA claimed nucleotide sequences themselves would have been obvious in view of conventional siRNA design methodology and the state of the RNA interference art.
The amendments materially change both the enablement and obviousness analyses. The new rejections under 35 U.S.C. §112(a) set forth below are scope-of-enablement rejections. They do not take the position that the specific murine, retinal, intravitreal siRNA embodiment actually demonstrated in the specification is itself nonenabled. The specification reasonably enables at least administration of the expressly recited TPM1-specific siRNA duplexes by intravitreal injection to the rd10 mouse retina and demonstrates reduction of retinal inflammatory markers, reduction of photoreceptor degeneration, and improvement of retinal electrophysiological function. As to claims 7 and 9, the disclosure likewise reasonably enables at least an injectable, directly administered siRNA-solution embodiment falling within the recited immediate-release/injection alternatives.
The §112(a) rejections instead address the additional breadth of the pending claims beyond those enabled embodiments, including unrestricted species encompassed by “subject,” therapeutic endpoints extending beyond the retinal-degeneration context actually demonstrated, the controlled-release branch of claim 7, and the materially different non-injection delivery platforms encompassed by claim 9.
Consistent with this distinction, the new §103 rejection below is directed to enabled embodiments encompassed by the claims, including the mouse TPM1 siRNA species, intravitreal aqueous siRNA administration, the immediate-release/injection alternatives, reduction of TPM1-associated retinal inflammation, and preservation or rescue of retinal function. The §103 rejection does not depend upon the non-mouse, non-retinal, controlled-release, or non-injection subject matter identified below as exceeding the scope reasonably enabled by the specification. Thus, the §112(a) and §103 rejections address different portions of the breadth encompassed by the pending claims and do not depend upon inconsistent factual premises.
New Rejections
The following new rejections are made from the previous Office Correspondence dated 18 May 2026, as the Applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Objections
Claims 7 and 9 9 are objected to because of the following informalities:
Claim 7 recites that “the pharmaceutical composition is formulated to an administration form selected from an immediate-release form or a controlled-release form.” The phrase “formulated to an administration form” is grammatically improper. Appropriate correction is required. For example, the claim may be amended to recite that the pharmaceutical composition is “formulated as an administration form” or “formulated in an administration form” selected from an immediate-release form or a controlled-release form.
Claim 9 recites the phrase, “drug-loaded contact lenses form”, which lacks grammatical agreement between the plural noun “lenses” and singular “form.” When used adjectivally to modify “form,” the singular “lens” is appropriate (e.g., “a drug-loaded contact lens form”). The applicant is advised to amend the phrase to, for example, “drug-loaded contact lens form.”
In addition, claim 9 recites, “a nanoparticle-mediated delivery” omits the word “form,” breaking the parallel structure of the list of administration forms. The claim should be amended to read “a nanoparticle-mediated delivery form.”
Claim Rejections - 35 USC § 112(a)
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 10 and 11 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 enablement requirement. The claim 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. The specification reasonably enables use of the specifically recited TPM1-targeting siRNAs in the rd10 mouse retinal-degeneration model, administered intravitreally, to reduce retinal inflammatory pathology and ameliorate decline in retinal function. The present rejection does not question enablement of that disclosed murine retinal embodiment. Rather, claims 10 and 11 extend materially beyond that enabled species, and the scope of protection sought by the claims is not commensurate with the scope reasonably enabled by the specification.
The specification, while providing an enabling disclosure for use of the recited TPM1-targeting siRNA duplexes in a murine rd10 model of retinitis pigmentosa, does not describe the claimed invention in such full, clear, concise terms as to enable a person of ordinary skill in the art to practice the claimed therapeutic methods throughout the unrestricted species scope encompassed by the term “subject” without undue experimentation.
The relevant inquiry is whether the disclosure teaches one of ordinary skill to make and use the full “subject” scope of the claimed invention without undue or unreasonable experimentation (see MPEP § 2164, 2164.01(a), 2164.06, and 2164.08). The enablement determination has been made under the factors set forth in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988) as detailed below:
Breadth of the claims- Claim 10 recites broadly, “A method for reducing neuroinflammation in a subject in need thereof, comprising administering the composition of claim 1 to the subject.” Claim 11 similarly recites “A method for rescuing visual function in a subject in need thereof, comprising administering the composition of claim 1 to the subject.” Neither claim restricts “subject” to Mus musculus, to the rd10 mouse, or even to a mammalian species whose relevant TPM1 transcript contains an operative target sequence for at least one of the three fixed siRNA duplexes. Moreover, claim 10 does not expressly limit “neuroinflammation” to retinal neuroinflammation associated with retinal degeneration, and claim 11 does not expressly limit the visual dysfunction being rescued to visual dysfunction caused by retinal degeneration or photoreceptor degeneration. The claims therefore encompass substantially more than the species and disease context actually demonstrated.
The specification’s working disclosure is materially narrower. Example 2 expressly employs the rd10 mouse and administers the presently claimed TPM1-specific siRNAs by intravitreal injection. The specification reports TPM1 knockdown accompanied by reductions in inflammatory markers, reduction in retinal glial activation, reduction of photoreceptor death, and improvement in ERG parameters. Accordingly, the disclosure supplies an operative teaching for the rd10 mouse species, retinal degeneration, retinal neuroinflammation associated with that degeneration, intravitreal administration of the claimed TPM1 siRNA, and retinal electrophysiological dysfunction associated with the rd10 degenerative phenotype. The disclosure does not provide corresponding working examples or a species-generalizing technical teaching demonstrating the same therapeutic operation across the unrestricted “subject” genus or across neuroinflammatory and visual disorders unrelated to retinal degeneration.
The breadth discrepancy is particularly material because amended claim 1 does not permit selection of whatever TPM1 siRNA may be appropriate for a particular species. The claim is closed to three fixed duplexes comprising SEQ ID NOS. 17/18, 19/20, or 21/22. RNA interference is sequence dependent. The specification therefore cannot generalize the successful rd10 mouse result merely by referring to the homologous gene TPM1 in another species. The Examiner’s comparison with human TPM1 RefSeq NM_001018005.2 illustrates this point:
siTPM1-1
Claimed target core:
5′-GATGAACTGGACAAATACT-3′
Human TPM1 corresponding sequence:
5′-GATGAACTGGACAAATACT-3′
Identity: 19/19
siTPM1-2
Claimed target core:
5′-GATCAGTAACCAAATTGGA-3′
Human TPM1 corresponding sequence:
5′-GGTCAGTAACTAAATTGGA-3′
Identity: 17/19
siTPM1-3
Claimed target core:
5′-GAAAAGCATTGATGACTTA-3′
Human TPM1 corresponding sequence:
5′-GAAAAGCATTGATGACTTA-3′
Identity: 19/19
The Examiner therefore does not contend that the claimed siRNAs are categorically incapable of inhibiting human TPM1. Indeed, the comparison provides a sound sequence basis for investigating siTPM1-1 and siTPM1-3 in at least the examined human TPM1 transcript.
The significance for enablement is instead that the claim extends to an unrestricted species genus while the therapeutic molecules are fixed sequence-dependent reagents. Even within the mouse-to-human comparison, the three claimed alternatives do not present identical target conservation. The specification contains no general rule establishing that the same fixed duplexes have an operative TPM1 target in every species encompassed by “subject.”
Nature of the invention (sequence dependence of RNA interference)- The prior art established general RNAi principles and made sequence alignment and knockdown assays conventional. This level of ordinary skill supports enablement of embodiments reasonably predictable from the disclosed species; it does not, however, enlarge the specification into a disclosure of an unrestricted biological genus where the existence and sequence of the operative target site are themselves species dependent. The scope problem is therefore not that the skilled artisan could not perform sequence alignment or conduct an RNAi assay. Rather, the disclosure does not identify a representative range of non-mouse species or provide a common sequence/biological principle demonstrating that the same three fixed duplexes operate throughout the claimed subject genus. Similarly, for claim 10, the specification provides evidence connecting TPM1 knockdown to retinal inflammatory markers in the rd10 model, but does not establish that the claimed fixed siRNAs reduce neuroinflammation generally in anatomically and etiologically different neuroinflammatory conditions. For claim 11, the disclosure establishes improvement of ERG function in the rd10 retinal-degeneration model, but does not establish that TPM1 inhibition rescues visual dysfunction irrespective of the cause of the impairment.
State of the prior art (sequence evidence)- The specification expressly identifies the three siRNAs used in Example 2 as siTPM1-1: SEQ ID NOS. 17 and 18; siTPM1-2: SEQ ID NOS. 19 and 20; and siTPM1-3: SEQ ID NOS. 21 and 22. The specification further identifies mouse TPM1 accession NM_001164255.1 in the experimental section and reports that TPM1 was knocked down by intravitreal administration of these TPM1-specific siRNAs in rd10 mice.
Comparison of the 19-nucleotide target-recognition portions of the claimed siRNAs, excluding their terminal TT overhangs, with the human TPM1 Tpm1.1 transcript corresponding to RefSeq NM_001018005.2 yields the following:
siTPM1-1 target core:
Mouse/claimed: 5'-GATGAACTGGACAAATACT-3'
Human TPM1: 5'-GATGAACTGGACAAATACT-3'
Identity: 19/19 (100%)
siTPM1-2 target core:
Mouse/claimed: 5'-GATCAGTAACCAAATTGGA-3'
Human TPM1: 5'-GGTCAGTAACTAAATTGGA-3'
Identity: 17/19 (89.5%)
siTPM1-3 target core:
Mouse/claimed: 5'-GAAAAGCATTGATGACTTA-3'
Human TPM1: 5'-GAAAAGCATTGATGACTTA-3'
Identity: 19/19 (100%)
The alignment therefore provides a sequence-based reason why a skilled artisan might reasonably investigate siTPM1-1 and siTPM1-3 for human TPM1 knockdown. However, this sequence conservation does not establish enablement throughout the unrestricted genus of “subjects,” nor does it demonstrate that each of the three claimed alternatives is therapeutically operative in humans.
In particular, siTPM1-2 differs from the corresponding human TPM1 sequence at two of nineteen target-recognition positions. When considered from the antisense guide orientation, one of these differences falls in or immediately adjacent to the central guide region associated with AGO2-mediated target cleavage. Because siRNA mismatch effects are position- and sequence-dependent, the disclosure provides no basis for determining whether SEQ ID NOS. 19/20 retain sufficient human TPM1 knockdown activity to function therapeutically. More importantly, the specification provides no corresponding sequence comparison, knockdown experiment, or therapeutic data for the other non-mouse species encompassed by the unrestricted term “subject.”
Amount of direction provided- The amount of direction provided is substantial for the enabled mouse-retina species but falls off sharply outside that species. The specification identifies the rd10 mouse model, the claimed TPM1 siRNAs, intravitreal administration, an approximate injection volume and dosing schedule, retinal inflammatory-marker measurements, photoreceptor-death measurements, and ERG measurements. The specification does not identify a representative set of additional species for which the same fixed siRNAs are operative, does not identify a general TPM1 target-site feature shared throughout the claimed subject genus, and does not establish that neuroinflammation or visual dysfunction outside the disclosed retinal-degeneration context is TPM1 responsive. The absence of such a generalizing teaching is what causes the enabled disclosure to be narrower than the claim scope.
Working examples- The sole working therapeutic example employing the presently claimed siRNAs is murine. Example 2 uses the rd10 mouse model of RP and reports TPM1 knockdown following intravitreal siRNA administration, accompanied by decreases in retinal inflammatory markers, decreased retinal glial activation, decreased photoreceptor death, and improvement in ERG responses. The specification itself characterizes rd10 mice as a model for human RP. However, demonstration that a mouse disease phenotype model aspects of human RP does not by itself demonstrate that every fixed nucleotide therapeutic used in the mouse possesses the required molecular target recognition, pharmacologic activity, dosing characteristics, and therapeutic efficacy across every species encompassed by “subject.” The nucleotide comparison discussed above illustrates the distinction. Two of the three target sequences happen to be exactly conserved in the examined human TPM1 transcript, whereas the third is not. Sequence conservation therefore must be evaluated at the level of each siRNA/target pair rather than inferred merely from conservation of the TPM1 protein or similarity of the retinal disease phenotype.
Predictability of the art- Although the basic principles of RNA interference were well developed, whether a particular fixed siRNA will silence a given species’ TPM1 transcript to a therapeutically sufficient degree depends upon more than identification of the same gene symbol in the two species. Relevant considerations include the target-site nucleotide sequence, TPM1 transcript and splice-variant usage, accessibility of the target site, guide-target mismatch position and identity, retinal cellular expression, intracellular siRNA availability, dose, and the amount of knockdown needed to produce the claimed physiological effect. The actual human sequence comparison confirms the sequence-specific nature of the issue (i.e., two claimed target sites are perfectly conserved while the third contains two substitutions). The specification contains no data establishing the functional consequence of the latter mismatches.
Level of ordinary skill- A person of ordinary skill would have been capable of obtaining TPM1 sequences from known sequence databases, aligning the claimed siRNAs with candidate transcripts, and experimentally measuring TPM1 knockdown. That level of skill, however, does not itself provide the missing answer as to whether a mismatched siRNA will retain therapeutically sufficient activity or whether the fixed claimed duplexes will function across all other species encompassed by “subject.” One of ordinary skill in the art would have to determine operability experimentally where sufficient complementarity or biological activity had not already been established.
Quantity of experimentation- Practicing the disclosed rd10 mouse embodiment species is treated as enabled. Rather, the undisclosed breadth separating the demonstrated species from the claimed genus requires undue experimentation. The claim covers combinations of fixed siRNA sequences, different species and TPM1 transcripts, and, for claims 10 and 11, therapeutic conditions materially broader than the retinal-degeneration phenotype actually demonstrated. The specification provides no representative series or generally applicable principle by which those additional portions of the claim scope are established as operative. The rejection therefore rests on the mismatch between the scope demonstrated and reasonably generalized by the disclosure and the materially broader scope of protection sought, not on an assertion that the disclosed murine retinal embodiment itself was technologically difficult to practice.
To practice the claims throughout their unrestricted species scope, the skilled artisan would first have to identify the relevant TPM1 retinal transcript or transcripts in each species, compare each fixed claimed siRNA against those transcripts, determine whether mismatched candidates retain sufficient target engagement and AGO2-mediated silencing, measure TPM1 knockdown in relevant retinal cells; determine suitable ocular dosing and delivery, and establish whether the degree of knockdown produces the claimed reduction of neuroinflammation or rescue of visual function. Where a species does not contain an adequately targetable sequence for any one of the fixed claimed duplexes, merely designing a new species-specific siRNA would not constitute practice of the present claims because amended claim 1 is restricted to SEQ ID NOS. 17-22. Thus, unlike a claim broadly permitting the skilled artisan to redesign the RNAi molecule for each species, the claims lock the therapeutic agent to three fixed sequences while leaving the biological subject unrestricted.
The present enablement issue is analogous in relevant respects to Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362 (Fed. Cir. 1999) (see also MPEP § 2164.06(b); hereinafter “Enzo”). In Enzo, antisense gene-regulation technology was demonstrated in a limited biological system, but the claims extended across a substantially broader range of organisms. The Federal Circuit concluded that the narrow working disclosure, unpredictability of antisense regulation, and experimentation required to adapt the technology beyond the demonstrated organisms did not enable the full scope.
The significance of Enzo here is not that every organism requires an example, but that a sequence-dependent gene-regulation disclosure must provide a reasonable basis for the breadth actually claimed. The present rejection does not rest merely on the absence of an example in every species. Rather, the molecular therapeutic agent is itself a fixed sequence-dependent RNAi reagent, while the claim contains no corresponding limitation ensuring that the recited target site exists and is functionally targetable in every encompassed subject.
In conclusion, The specification reasonably enables at least administration of the claimed TPM1 siRNAs to the rd10 mouse retina to reduce retinal inflammatory pathology and ameliorate retinal functional decline. Claims 10 and 11, however, are not limited to that enabled scope. Claim 10 extends to reducing “neuroinflammation” in an unrestricted “subject,” and claim 11 extends to rescuing visual function in an unrestricted “subject,” without restricting the endpoint to the retinal-degeneration context actually demonstrated. Accordingly, claims 10 and 11 are rejected under 35 U.S.C. §112(a) because the scope of enablement provided by the specification is not commensurate with the scope of the claims.
The applicant may overcome the rejection by appropriately limiting claim 10, for example, to reducing retinal neuroinflammation associated with retinal degeneration in an enabled subject population, and claim 11 to rescuing visual function impaired by retinal degeneration in an enabled subject population, provided such amendments are supported by the originally filed disclosure.
Claims 7 and 9 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 enablement requirement. The claim 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. The specification reasonably enables at least an injectable siRNA-solution embodiment administered intravitreally. The rejection concerns the additional claim breadth, wherein the specification is not commensurate with the full scope of the release-form and ocular-delivery alternatives recited in those claims.
The specification, while being enabling for at least an intravitreal administration of a solution containing TPM1-specific siRNA in the rd10 mouse model, does not reasonably provide enablement for the full scope of the controlled-release and diverse ocular-delivery embodiments encompassed by claims 7 and 9. To the extent claim 7 encompasses a directly administered solution as an “immediate-release form,” and claim 9 encompasses such a composition as an “injection form,” those species are not the subject of the present enablement deficiency.
The determination of enablement is made in view of the factors set forth in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). The inquiry is directed towards whether the specification teaches one of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation (see MPEP §§ 2164, 2164.01, and 2164.08), as detailed below:
Breadth of the claims- Claim 7 encompasses an immediate-release form or a controlled-release form. The specification’s working example administers TPM1 siRNA in solution directly into the vitreous. The disclosure therefore provides a concrete immediate-administration species. In contrast, the controlled-release discussion is generic. Although the specification refers to sustained-, delayed-, pulsed-, matrix-, and controlled-release concepts, it does not provide a controlled-release ocular formulation containing any of SEQ ID NOS. 17-22, identify a particular release-controlling matrix for those duplexes, provide a demonstrated retinal release profile, or identify an ocular release rate correlated with TPM1 knockdown. The scope problem is therefore the unsupported controlled-release limitation, not the disclosed directly injectable solution species.
Claim 9 is considerably broader and encompasses injecttion form, eye drop form, eye ointment form, hydrogel form, ultrasonic ocular drug-delivery form, drug-loaded contact lens form, drug-eluting implant form, nanoparticle-mediated delivery, intravitreal gene therapy form, and intravitreal microneedle form. The specification supplies a working intravitreal injection species. The present rejection does not contend that an injectable TPM1-siRNA composition itself is nonenabled. However, the remaining alternatives are materially different technology classes. The specification names and generally describes these alternatives but does not provide representative working embodiments or a common formulation/delivery principle showing that the fixed SEQ ID NO. 17–22 duplexes can be practiced throughout those diverse classes.
For example, the disclosure does not provide a particular TPM1-siRNA-containing drug-eluting implant, a TPM1-siRNA contact-lens formulation, an operative ultrasound regimen for delivery of the claimed duplexes, an intravitreal microneedle system containing the claimed duplexes, or a viral expression construct that generates the specifically recited duplex of claim 1. The “intravitreal gene therapy form” particularly illustrates the breadth discrepancy. The specification discusses viral vectors or nanoparticles transporting therapeutic genes, whereas amended claim 1 requires that the TPM1 inhibitor is one of three particular siRNA duplexes. The disclosure does not identify a viral construct, promoter, precursor RNA, or processing architecture that produces the claimed duplex.
Nature of the invention- The invention concerns therapeutic delivery of sequence-specific double-stranded siRNA to retinal tissue. Successful practice requires more than placing a nucleic acid in an ocular dosage form. The siRNA must remain sufficiently intact, reach the relevant retinal tissue and cells, become available intracellularly for RNA-interference activity, inhibit TPM1 to a therapeutically meaningful degree, and produce the claimed therapeutic effect.
The specification itself recognizes the importance of delivery across the cornea and/or blood-retinal barrier and identifies efficient, tissue-compatible, target-specific, and controlled delivery as desired properties of the contemplated ocular systems. Thus, the nature of the claimed invention necessitates a substantial enabling disclosure for each materially different delivery platform.
State of the prior art- A high level of general knowledge concerning ocular formulation does not, by itself, supply the information absent from the instant specification as to how the particular SEQ ID NO. 17-22 siRNAs are to be formulated and delivered throughout the entire scope of claims 7 and 9. Prior-art knowledge may supplement a disclosure, but the specification must still provide sufficient integration and direction where the claimed combination is not self-evident (see MPEP § 2164). The mere fact that individual delivery technologies were independently known does not establish that a skilled artisan could employ each such technology with the claimed TPM1 siRNAs, for retinal TPM1 knockdown, without substantial development work.
Level of ordinary skill- A person of ordinary skill would reasonably possess substantial knowledge of molecular biology, RNA interference, ophthalmic formulation, and/or ocular drug delivery. However, the level of skill does not supply the missing formulation-specific parameters necessary to practice the full scope of the claim. For example, one of ordinary skill in the art would still have to determine appropriate siRNA loading, stabilizing components, carrier composition, release characteristics, tissue penetration, intracellular uptake, dose, administration parameters, retinal biodistribution, and therapeutic exposure for materially different delivery systems.
Predictability of the art- The claimed subject matter involves the interaction of sequence-specific RNAi, ocular pharmacokinetics, biological barriers, intracellular delivery, and retinal pathology. The success of an intravitreal siRNA solution does not establish that the same siRNA will predictably remain active when incorporated into an eye drop, ointment, contact lens, hydrogel, implant, nanoparticle system, ultrasound-assisted system, gene-therapy system, or microneedle system. The different embodiments require different mechanisms for release, penetration, localization, and intracellular availability. Thus, practice across the claimed scope cannot reasonably be treated as merely substituting one conventional carrier for another.
Amount of direction or guidance provided- The specification provides generalized descriptions of the claimed delivery alternatives, but does not supply the technical parameters required for practicing them with the claimed TPM1 siRNAs. For example, the specification states generally that drug-eluting implants may release drugs over an extended period, nanoparticles may encapsulate drugs and improve bioavailability, ultrasound may transiently disrupt barriers, viral vectors or nanoparticles may transport therapeutic genes, and microneedles may penetrate the retina. However, no particular implant composition, nanoparticle composition or size, siRNA loading level, surface modification, hydrogel composition, contact-lens material, microneedle geometry, ultrasound intensity, frequency or duration, or viral expression construct corresponding to SEQ ID NOS. 17-22 is disclosed.
The ultrasound embodiment is particularly illustrates this point. The disclosure states only that ultrasound waves may enhance penetration and transiently disrupt barriers. It does not teach the intensity, frequency, duration, or other operating conditions sufficient to deliver a therapeutically effective amount of the claimed siRNA to the relevant retinal cells. The disclosure does not teach the conditions necessary to select sufficient ultrasonic energy for the claimed biological treatment (see MPEP § 2164.06(b)).
Likewise, the specification describes “intravitreal gene therapy” as involving viral vectors or nanoparticles for transporting therapeutic genes, whereas presently amended claim 1 requires that the TPM1 inhibitor is one of three particular siRNA duplexes. The specification does not identify a viral construct, promoter, precursor RNA sequence, processing arrangement, or other expression system that would generate the recited SEQ ID NO. 17/18, 19/20, or 21/22 duplex in retinal cells.
With respect to controlled release, the specification discusses matrix technology, sustained-, delayed-, pulsed-, and immediate-release concepts in generic terms. It does not provide an ocular controlled-release formulation containing SEQ ID NOS. 17-22, identify a matrix material for the claimed siRNA, establish siRNA stability during prolonged release, identify an ocular release rate producing TPM1 knockdown, or demonstrate a relationship between release kinetics and retinal therapeutic exposure. Indeed, portions of the controlled-release discussion define performance by reference to systemic plasma concentrations rather than retinal siRNA exposure.
Working examples- The specification contains a pertinent working example, but that example is substantially narrower than claims 7 and 9. Example 2 administers TPM1-specific siRNA to rd10 mice by intravitreal injection. The three presently claimed siRNA duplexes are expressly listed as SEQ ID NOS. 17-22. Approximately 1 μL of siRNA solution is injected into the vitreous, three administrations are performed at two-day intervals, and subsequent experiments demonstrate TPM1-related changes in retinal inflammation, photoreceptor survival, and ERG responses.
However, the specification provides no working example using the claimed siRNA in an eye drop, an eye ointment, a hydrogel, an ultrasound-mediated ocular-delivery system, a drug-loaded contact lens, a drug-eluting implant, a nanoparticle delivery system, an intravitreal gene-therapy system, or an intravitreal microneedle system. The specification also does not provide a working controlled-release formulation of the claimed TPM1-specific siRNA.
Quantity of experimentation necessary- In order to practice the undisclosed portions of claims 7 and 9, one of ordinary skill in the art would be required to select or develop the particular carrier or delivery platform; determine siRNA loading, stability, and release; determine retinal penetration and biodistribution; establish intracellular delivery; establish TPM1 knockdown; determine dose and administration conditions; assess toxicity; and establish therapeutic efficacy.
For several claim 9 alternatives, one of ordinary skill in the art would additionally be required to determine device- or technology-specific parameters such as ultrasound conditions, implant composition, nanoparticle characteristics, contact-lens release properties, microneedle geometry, or a gene-expression construct. The experimentation is therefore not simply confirmation of an otherwise fully taught embodiment. Rather, the specification leaves one of skill in the art to develop materially different delivery systems and then determine whether each one successfully delivers the claimed sequence-defined siRNA to retinal cells in a biologically active form.
In summary, when the Wands factors are weighed as a whole, the specification is reasonably enabling for the demonstrated intravitreal siRNA-solution embodiment, but does not enable the full scope of the controlled-release and ocular-delivery platforms encompassed by claims 7 and 9 without undue experimentation. The relevant Wands factors therefore weigh differently for different portions of the claim. For the directly injectable siRNA solution, the disclosure provides substantial direction and an actual working example. That species is treated as enabled. For the controlled-release and non-injection claim limitations, the specification provides principally high-level identification of diverse technologies rather than representative TPM1-siRNA formulations or a generalizable teaching tying those technologies to the fixed claimed duplexes.
The rejection does not depend upon an assertion that a skilled artisan could not understand what an implant, nanoparticle, hydrogel, ultrasound system, contact lens, or microneedle is. Rather, the problem is that the claims aggregate numerous distinct platform classes while the application provides an operative teaching for only a substantially narrower delivery species and does not provide a representative disclosure commensurate with the remainder of the claimed genus. Accordingly, claims 7 and 9 are rejected under 35 U.S.C. §112(a) for lack of enablement commensurate with claim scope.
For clarity, the enabled immediate-release/injection species encompassed by claims 7 and 9 is separately addressed under §103 below. The §103 rejection does not rely upon the controlled-release, eye-drop, ointment, contact-lens, implant, ultrasonic, nanoparticle, gene-therapy, or microneedle branches identified here as exceeding the demonstrated scope of enablement.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which Applicant regards as his invention.
Claims 6, 7, and 9 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 6 is directed to a pharmaceutical composition, but further recites, “wherein the pharmaceutical composition is delivered through an approach selected from an intravitreal injection, a subretinal injection or a suprachoroidal injection.” A claim to a composition may refer to the process in which the composition is intended to be used where it remains clear that the claim is directed to the product rather than the process. However, a single claim that requires both a product and affirmative steps of using the product may be indefinite where the language creates uncertainty as to what conduct satisfies the claim (see MPEP § 2173.05(p); In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318 (Fed. Cir. 2011); see also IPXL Holdings, L.L.C. v. Amazon.com, Inc., 430 F.3d 1377 (Fed. Cir. 2005)).
The wording of claim 6 does not merely state that the composition is formulated for, adapted for, or suitable for administration by a particular route. Instead, the claim affirmatively states that the composition “is delivered” through one of three identified injection approaches. The specification confirms that these recitations concern affirmative administration procedures. Intravitreal injection is described as injecting the drug directly into the vitreous humor, subretinal injection is described as a surgical procedure involving injection into the subretinal space, and suprachoroidal administration is described as an in-office injection delivering the composition behind the retina.
The claim therefore permits at least two materially different reasonable interpretations wherein claim 6 is satisfied by a pharmaceutical composition having characteristics that make it suitable for administration through one of the recited routes, regardless of whether administration actually occurs, or claim 6 is not satisfied unless and until the composition is actually delivered by intravitreal, subretinal, or suprachoroidal injection. The claim language does not reasonably inform the public whether the claimed subject matter is the pharmaceutical composition itself or the pharmaceutical composition in combination with performance of an administration step.
Claims 7 and 9 depend from claim 6 and do not cure this ambiguity. Accordingly, claims 6, 7, and 9 are rejected under 35 U.S.C. § 112(b). The rejection may be overcome, for example, by amending claim 6 to recite, “wherein the pharmaceutical composition is formulated for administration by an approach selected from intravitreal injection, subretinal injection, and suprachoroidal injection,” provided such language is adequately supported by the originally-filed disclosure. Alternatively, the applicant may pursue the actual administration step in a method claim.
Claim 9 is further rejected as indefinite because the term “administration form,” as applied to the alternatives recited in claim 9 and when considered together with the limitations incorporated from claims 6 and 7, fails to provide reasonably certain claim boundaries. Claim 9 depends from claim 7, which depends from claim 6. Claim 9 therefore incorporates all limitations of both claims 6 and 7.
Claim 6 requires that the composition “is delivered” by an approach selected from intravitreal injection, subretinal injection, or suprachoroidal injection. Claim 7 then recites that the pharmaceutical composition is formulated to “an administration form” selected from an immediate-release form or controlled-release form. Claim 9 refers back to “the administration form” and requires that it “is” selected from an injection form, eye drop form, eye ointment form, hydrogel form, ultrasonic ocular drug delivery form, drug-loaded contact lens form, drug-eluting implant form, nanoparticle-mediated delivery, intravitreal gene therapy form, or intravitreal microneedle form.
Therefore, the resulting claim 9 is indefinite for at least the following reasons:
“Administration form” encompasses different categories of subject matter. The recited alternatives are not all reasonably characterized as the same type of “form.” For example, “injection form,” “eye drop form,” “eye ointment form,” and “hydrogel form” reasonably describe dosage or physical formulation forms; “drug-loaded contact lens” and “drug-eluting implant” reasonably describe devices or device-associated dosage systems; “ultrasonic ocular drug delivery” reasonably describes a method or technique for assisting delivery; “nanoparticle-mediated delivery” reasonably describes a delivery mechanism or carrier technology; and “intravitreal gene therapy” reasonably describes a therapeutic/delivery modality rather than a physical dosage form.
The specification itself recognizes this categorical distinction. It states that the choice of the “delivery method” depends upon factors including the “administration form,” thereby treating delivery method and administration form as conceptually separate considerations, but subsequently places delivery methods, devices, dosage forms, and gene therapy together under the heading of administration forms. It is therefore unclear what characteristic of the claimed pharmaceutical composition must be examined to determine whether it possesses one of the recited “administration forms.”
Claim 9 conflicts with the injection requirement inherited from claim 6. Because claim 9 depends through claim 7 from claim 6, every embodiment of claim 9 incorporates the requirement that the pharmaceutical composition “is delivered” by intravitreal, subretinal, or suprachoroidal injection. Claim 9 nevertheless permits the administration form to be, inter alia, an eye drop, eye ointment, drug-loaded contact lens, drug-eluting implant, or ultrasonic ocular drug-delivery form.
The specification itself describes several of these as alternative delivery approaches. For example, implants may be surgically placed in the eye, ultrasound is used to facilitate penetration, contact lenses are separately identified as a delivery system, and the specification introduces different administration forms in addition to the conventional injection techniques.
Consequently, it is unclear whether a composition in an eye-drop, ointment, contact-lens, implant, ultrasound-assisted, or other claim 9 form must nevertheless also be actually injected by one of the claim 6 routes; or claim 9 is intended to permit the selected alternative to replace the injection approach inherited from claim 6. The second interpretation would be inconsistent with the dependent-claim requirement that claim 9 incorporate all limitations of the claims from which it depends, whereas the first construction results in combinations whose relationship is not explained by the claim. This ambiguity prevents one of ordinary skill from determining the metes and bounds of the claim with reasonable certainty.
Claim 7 and claim 9 use the same “administration form” term for different characteristics. Claim 7 defines “the administration form” according to release behavior (i.e., immediate release or controlled release). Claim 9 then defines that same “administration form” according to a different set of characteristics (i.e., physical dosage form, device, carrier, delivery technology, or therapeutic modality). A controlled-release drug-eluting implant, for example, can reasonably possess both classifications. In contrast, “ultrasonic ocular drug delivery” describes no readily ascertainable physical release form at all. Thus, it is unclear whether claim 9 further characterizes the same administration form recited in claim 7 or introduces a second, conceptually distinct limitation.
“Intravitreal gene therapy form” is additionally unclear in the context of amended claim 1. Amended claim 1 specifically requires that the TPM1 inhibitor is a siRNA comprising one of the recited sense/antisense strand pairs of SEQ ID NOS. 17-22. The specification, however, describes “intravitreal gene therapy” as employing viral vectors or nanoparticles to transport therapeutic genes. It is therefore unclear whether “intravitreal gene therapy form” in claim 9 refers to a formulation containing the preformed claimed siRNA duplex, a viral or other vector encoding an RNA precursor from which the claimed siRNA is generated, a nanoparticle carrying the claimed preformed siRNA, a therapeutic gene whose expression indirectly affects TPM1, or another nucleic-acid therapy. These are materially different compositions and mechanisms, and neither claim 9 nor the incorporated claims provide an objective boundary for determining what qualifies as the claimed “intravitreal gene therapy form.”
In summary, because the term “administration form” is used to encompass different categories of subject matter and because the claim 9 alternatives create uncertainty when combined with the inherited injection and release-form limitations, one of ordinary skill would be faced with more than one reasonable interpretation of the scope of claim 9. Accordingly, claim 9 is rejected as indefinite under 35 U.S.C. § 112(b).
The applicant may overcome the rejection by restructuring the claim set so that separate dependent claims are directed, as appropriate, for example to dosage or formulation forms, release characteristics, delivery vehicles or carriers, devices, and administration methods or routes, with each claim depending from a parent claim containing compatible limitations with the inherited route, or by restructuring the claim hierarchy so that topical, contact-lens, ultrasonic, implant, nanoparticle, and injection embodiments are not required to inherit an inconsistent route-of-administration limitation.
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.
Claims 1, 5-7, and 9-11 are rejected under 35 U.S.C. § 103 as being unpatentable over Li, Liang, and Lin (Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice. Aging Cell. 2022 Mar;21(3):e13566, published electronically 11 Feb 2022, hereinafter “L3”), in view of Eupheria Biotech GmbH, mTpm1, Catalog No. MU-03366-1 (published 2010; also published as Sigma Product ID EMU033661, hereinafter referred to as “Eupheria”), in further view of Ui-Tei et al. (Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. Nucleic Acids Res. 2004 Feb 9;32(3):936-48; hereinafter “Ui-Tei”), NCBI RefSeq database Mus musculus mRNA NM_001164255.1 (Nucleotide. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. Accession No. NM_001164255.1, Mus musculus tropomyosin 1, alpha (Tpm1), transcript variant Tpm1.10, mRNA; 1988-2026; hereinafter “NCBI RefSeq NM_001164255.1”), NCBI RefSeq database Mus musculus mRNA NM_001164250.1 (Nucleotide. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. Accession No. NM_001164250.1, Mus musculus tropomyosin 1, alpha (Tpm1), transcript variant Tpm1.7, mRNA; cited 1988-2026; hereinafter “NCBI RefSeq NM_001164250.1”), Naito et al. (siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W124-9; hereinafter “Naito”), Ackerman et. al (WO2022147249A1; published 07 July 2022, hereinafter “Ackerman”), Ding et al. (Systems Analyses Reveal Shared and Diverse Attributes of Oct4 Regulation in Pluripotent Cells. Cell Syst. 2015 Aug 26;1(2):141-51; hereinafter “Ding”), Kittler et al. (Genome-wide resources of endoribonuclease-prepared short interfering RNAs for specific loss-of-function studies. Nat Methods. 2007 Apr;4(4):337-44; hereinafter “Kittler”), Rashid et al., “Microglia in Retinal Degeneration,” Frontiers in Immunology 10:1975, 2019; hereinafter “Rashid”, and Taniguchi et al. (Novel use of a chemically modified siRNA for robust and sustainable in vivo gene silencing in the retina. Sci Rep. 2020 Dec 18;10(1):22343; hereinafter “Taniguchi”).
The present rejection is based upon enabled species encompassed by the pending claims. Specifically, the rejection relies upon the sequence-defined TPM1 siRNA species corresponding to SEQ ID NOS. 21/22, a mouse/retinal therapeutic context, an aqueous injectable siRNA composition, intravitreal administration, the immediate-release/injection-form alternatives of claims 7 and 9, reduction of TPM1-associated retinal inflammation, and amelioration of retinal functional decline.
L3 teaches that increased TPM1 is associated with inflammatory and functional abnormalities in the retina and expressly investigates therapeutic neutralization of TPM1 (Abstract). In particular, L3 section 2.5 teaches “Systemic administration of TPM1-specific neutralizing antibody counteracts age-related dendritic outgrowth and visual function decline in aged mice,” administering a TPM1-specific neutralizing antibody to aged mice, and reports amelioration of retinal structural and functional abnormalities. Li reports improved retinal electrophysiological function following TPM1 inhibition, including improvement of scotopic ERG parameters.
L3 further teaches in section 2.7, that TPM1 participates in retinal inflammatory signaling (FABP5/NF-κB signaling pathway). The L3 Abstract likewise reports that recombinant TPM1 accelerates glial activation, neuronal remodeling, and retinal functional decline, whereas anti-TPM1 neutralization ameliorates age-related structural and functional retinal changes.
Rashid explicitly links microglial activation and neuroinflammation to retinal degeneration pathologies, AMD and RP (pages 4-6, " Microglia in Age Related Macular Degeneration" section, reviewed in the entire section and “Microglia in Hereditary Retinopathies” section, first 4 paragraphs, respectively) and that targeting the modulation of microglial activation/inflammation is a promising therapeutic strategy for these diseases (pages 12-13, Conclusion section). Thus, teaching that retinal degeneration is mediated in substantial part by microglial activation, neuroinflammatory signaling, and inflammatory remodeling of retinal tissue. Rashid therefore provides additional motivation to target microglia-associated inflammatory pathways in retinal degenerative disease. However, Rashid does not teach TPM1 inhibition or TREM2 silencing.
Thus, L3 expressly supplies both the therapeutic target, TPM1, and the therapeutic reason for inhibiting that target in retinal tissue along with Rashid. L3 differs from instant claim 1 in that the experimentally administered TPM1 inhibitor is an antibody rather than one of the applicant’s specifically recited siRNA duplexes.
Ackerman teaches that TPM1 is susceptible to effective sequence-specific RNA-interference knockdown (shRNA; p. 56, ll.8-15; p. 57, Table 1O; p. 111, l. 17-p. 113, l. 2;FIG. 52), supplying an express teaching that TPM1 can be inhibited by an RNA-interference reagent. Specifically, Example 36, “Testing TPM1 shRNA,” and Figure 52, disclose co-transfection of TSA201 cells with TPM1-WT and six custom TPM1 shRNAs. TPM1 expression was measured by qRT-PCR. Ackerman identifies TPM1 shRNA Sh2, SEQ ID NO. 2751, corresponding RNA SEQ ID NO. 2752, as producing the strongest knockdown, approximately 85% TPM1 knockdown.
Thus, prior to the instant effective filing date, Ackerman provided experimental evidence that TPM1 was amenable to sequence-specific RNA-interference suppression, one of ordinary skill in the art could prepare a limited panel of custom TPM1 RNAi reagents, routine qRT-PCR screening could identify an effective TPM1-targeting sequence, and very substantial TPM1 suppression could be achieved.
Ackerman does not expressly disclose the instant claimed SEQ ID NOS. 17-22, but establishes that TPM1 itself was a known and successfully demonstrated RNAi target and that selection and screening of multiple TPM1 RNAi sequences was an established approach.
Ui-Tei supplies siRNA sequence-design teaching. Ui-Tei’s Abstract teaches the siDirect system for computing highly effective and target-specific mammalian siRNA sequences. Significantly, Ui-Tei states that an arbitrary target sequence can be entered and that the system rapidly returns candidate siRNAs suitable for, inter alia, therapeutic gene silencing.
Ui-Tei’s Introduction and Figure 1 identify four sequence characteristics for highly effective mammalian siRNAs: (1) A/U at the 5′ end of the antisense strand; (2) G/C at the 5′ end of the sense strand; (3) A/U-rich sequence in the 5′ terminal third of the antisense strand; and (4) absence of a GC stretch longer than nine base pairs. Ui-Tei states that siRNAs satisfying these four conditions produce highly effective RNA interference in mammalian cells.
Ui-Tei’s Methods section, “Selecting highly effective siRNA sequences,” explains that siDirect applies these Ui-Tei sequence-selection guidelines to identify effective siRNA candidates from the target sequence. Ui-Tei’s Figure 4 and accompanying text further teach the practical design workflow wherein an arbitrary mRNA sequence or accession number is entered; the system analyzes individual 19-nucleotide windows; and effective gene-specific siRNA candidates are returned. Ui-Tei explains that a complete candidate list for a typical mRNA can be generated within seconds. Thus, once one of ordinary skill in the art had the TPM1 mRNA sequence (such as from Ackerman), Ui-Tei supplied an express and routine procedure for selecting candidate TPM1 siRNA sequences.
NCBI RefSeq NM_001164255.1 and NCBI RefSeq NM_001164250.1 establish that the nucleotide sequence of mouse Tpm1 was publicly known. The identified RefSeq transcripts include NM_001164250.1 and NM_001164255.1, and the Tpm1 coding sequence contains the nucleotide windows to which the claimed siRNAs are complementary. Thus, the primary sequence from which TPM1-specific RNAi agents could be designed was not unknown.
The 19-nucleotide target-recognition portions of the three presently claimed siRNA duplexes, excluding the conventional terminal TT overhangs, conform to those published design criteria. SEQ ID NOS. 17/18 5′ sense base is G, 5′ antisense base is A, A/U in first 7 antisense bases is 6/7, and does not have a >9-base GC stretch. SEQ ID NOS. 19/20 5′ sense base is G, 5′ antisense base is U, A/U in first 7 antisense bases is 5/7, and does not have a >9-base GC stretch. SEQ ID NOS. 21/22 5′ sense base is G, 5′ antisense base is U, A/U in first 7 antisense bases is 5/7, and does not have a >9-base GC stretch.
After accounting for the terminal overhang, each claimed sense strand begins with G, each corresponding antisense strand begins with A or U, each antisense strand possesses the required A/U enrichment in its 5′-terminal region, and none contains a prohibited long GC stretch. Accordingly, the claimed sequences are not being reconstructed solely from the applicant’s disclosure. They correspond to target windows in the known Tpm1 sequence and possess the exact sequence characteristics that Ui-Tei had previously taught to select when designing highly effective mammalian siRNAs.
Moreover, Ackerman expressly identifies human TPM1 RefSeq NM_001018005.2 as an exemplary TPM1 mRNA sequence. NCBI identifies that same accession as human TPM1 transcript variant Tpm1.1. Comparison of the known NM_001018005.2 sequence with the target-recognition cores of the amended claim shows that at least the siTPM1-1 and siTPM1-3 target cores correspond to perfectly complementary TPM1 target windows. The rejection therefore does not depend upon an assertion that a skilled artisan would have had to invent an unknown target sequence, but rather, the relevant TPM1 transcript itself was expressly identified in the RNAi prior art.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to replace L3’s TPM1-neutralizing antibody with a TPM1-directed RNA-interference reagent designed from the known TPM1 transcript. The references themselves supply the reason. L3 Abstract and section 2.5 teach that inhibiting TPM1 ameliorates retinal structural and functional abnormalities, L3 section 2.7 teaches that TPM1 participates in retinal inflammatory signaling through FABP5/NF-κB, pharmacological suppression of pathologically activated microglia is a therapeutic strategy. Ackerman Table IO and Example 36/Fig. 52, teaches sequence-specific RNA-interference suppression of TPM1 itself and experimentally demonstrates approximately 85% knockdown. Ui-Tei’s Introduction/Fig. 1 and Fig. 4, provides a routine procedure for selecting highly effective siRNA sequences from a known mRNA sequence, and NCBI RefSeq NM_001164255.1 and NCBI RefSeq NM_001164250.1 establish that the nucleotide sequence of mouse Tpm1 was publicly known.
The proposed modification therefore does not require changing the biological target identified by L3. It merely substitutes a known TPM1-suppression modality, RNA interference, for L3’s TPM1-neutralizing antibody, using a published sequence-selection technique. This is the application of a known technique to a known therapeutic target ready for improvement, as contemplated by KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-22 (2007) and MPEP § 2143.
A person of ordinary skill in the art would have had a reasonable expectation that a rationally selected TPM1 siRNA would suppress TPM1. Ackerman Example 36/Fig. 52 provides actual experimental evidence that a custom TPM1 RNA-interference sequence achieved approximately 85% TPM1 knockdown. Ui-Tei’s Introduction/Fig. 1 teaches objective sequence characteristics associated with highly effective mammalian RNA interference, and the presently claimed sequences conform to those characteristics. In addition, retinal tissue was already known to be amenable to sequence-specific siRNA silencing, as established by Taniguchi below. Accordingly, the sequence-specific limitation of instant claim 1 does not patentably distinguish the claimed composition.
Moreover, Eupheria’s product disclosure identifies Mus musculus mTpm1 mouse esiRNA (Catalog No.: MU-03366-1; see also Sigma Product ID: EMU033661) ant the esiRNA target-region sequence. The specific tpm1 rnai target region contains the claimed seq id no. 21 target core. The disclosed sequence contains...GATCAGTAACCAAATTGGAGAAAAGCATTGATGACTTA... The 19-nucleotide sequence GAAAAGCATTGATGACTTA is the DNA equivalent of the target-recognition portion of Applicant’s SEQ ID NO. 21 GAAAAGCAUUGAUGACUUA. The same Eupheria target region also contains GATCAGTAACCAAATTGGA, the DNA equivalent of the targeting portion of SEQ ID NO. 19. The current Eupheria product page expressly associates MU-03366-1 with Sigma EMU033661 and prints this sequence. The corresponding Sigma product page independently identifies EMU033661 as MISSION® esiRNA targeting mouse Tpm1, identifies NM_024427, provides the same cDNA target sequence, and explains that MISSION esiRNA is a heterogeneous mixture of siRNAs directed against the selected mRNA region.
The current electronic page does not itself display its original posting date. The examiner therefore relies on additional evidence to establish historical public accessibility. Thomas Hadlak, CEO of Eupheria Biotech GmbH, stated in written correspondence dated 11 August 2026 that MU-03366-1 has been part of Eupheria’s product portfolio since the company’s founding in 2010, its sequence has been fully disclosed on Eupheria’s website since that time, and the same product has been available since then through Sigma-Aldrich’s MISSION esiRNA portfolio. The Hadlak correspondence is relied upon as evidence establishing the historical public-accessibility date and continuity of the Eupheria electronic disclosure, not as the underlying technical prior-art disclosure.
This evidence is independently corroborated by Ding, published in 2015. Ding Supplementary Table S1, row 2822, identifies the specific reagent MU-03366-1, Tpm1 and associates that reagent with mouse Tpm1 RefSeq transcripts including NM_024427 and NM_001164255. The present draft already identifies that contemporaneous publication evidence.
Ding independently establishes that a specifically identified mouse Tpm1 esiRNA reagent was publicly available in the art well before the instant filing date. Ding’s Table S1, NIHMS815046-supplement-Table_S1.xlsx cell 2822, expressly identifies a particular esiRNA reagent MU-03366-1, Tpm1, and expressly associates that reagent with mouse Tpm1 RefSeq transcripts NM_001164248, NM_001164249, NM_001164250, NM_001164251, NM_001164252, NM_001164253, NM_001164254, NM_001164255, NM_001164256, and NM_024427.
Ding therefore provides dated evidence that, the art had progressed beyond merely knowing that the Tpm1 gene existed. A specifically identified mouse Tpm1 esiRNA reagent, MU-03366-1, targeting the Tpm1 transcript family that includes NM_024427 and NM_001164255, had been included in a publicly disclosed genome-scale RNAi reagent set (the specific instant claimed target-region sequence is currently associated with the commercial Sigma Aldrich EMU033661 MISSION® esiRNA targeting mouse Tpm1, with the same long cDNA target sequence that includes instant claimed siTPM1-2 core GATCAGTAACCAAATTGGA and instant claimed siTPM1-3 core GAAAAGCATTGATGACTTA, corresponding exactly, after DNA to RNA conversion and addition of the claimed TT overhangs, to the sense-strand targeting portions of SEQ ID NO. 19 and SEQ ID NO. 21; and Eupheria MU-03366-1. These commercially selected TPM1 RNAi target region has the exact instant claimed 19-nt target within that region). Thus, Ding supplies the narrower teaching that a particular predesigned esiRNA directed against mouse Tpm1 and the identified Tpm1 transcript family was publicly disclosed years prior to the instant effective filing date.
Kittler provides the technological foundation for the genome-scale esiRNA resources of Ding. Kittler teaches genome-wide datasets for production of esiRNAs for human, mouse, and rat, and states that an algorithm was used to predict an optimal region for esiRNA synthesis for every protein-coding gene in those species. Kittler further states that the investigators created the RiDDLE database for retrieval of target sequences and primer information (p. 337, Abstract and Introduction).
Kittler explains that DEQOR analysis showed efficient individual siRNAs to be nonuniformly distributed through transcript sequences and therefore sought to identify transcript fragments containing a high proportion of potent siRNAs. Kittler expressly states that the investigators identified optimal esiRNA target regions for protein-coding transcripts of the human, mouse, and rat genomes (p. 337, “In silico prediction of optimized esiRNAs”).
In Figure 1 (p. 338), Kittler describes the selection pipeline including identifying the longest common sequence among relevant transcript isoforms, performing DEQOR optimization, selecting an optimized target region, and designing primers for production of the esiRNA template. Figure 1 expressly labels DEQOR optimization as part of the pipeline and evaluates the percentage of “high-quality siRNAs” contained within each optimized target fragment. Most importantly, page 338 states that in the RiDDLE database, the primer pairs and sequence of the selected esiRNA target region were readily accessible to users, including for single-gene experiments and orthologous genes in different species.
Kittler therefore teaches that an esiRNA reagent was not based upon arbitrary digestion of an arbitrary part of an mRNA. Rather, the art deliberately computationally selected a transcript region enriched in predicted high-quality siRNA sequences. In the Discussion section (p. 340), Kittler further explains that the published primer sequences could be used to synthesize individual esiRNAs for small-scale experimentation and describes the resource as permitting rapid synthesis of esiRNAs for nearly all human, mouse, and rat genes.
Thus, Ding and Kittler together provide additional evidence that Tpm1 had already been embodied in a specifically selected RNAi reagent and that the underlying esiRNA technology deliberately selected target regions expected to yield multiple potent individual siRNA species.
Neither L3, Ding, Kittler, Ackerman, nor Ui-Tei explicitly states the instant claimed SEQ ID NOS. 17-22 verbatim. However, L3 expressly taught that TPM1 inhibition was therapeutically desirable in retina; Ackerman expressly demonstrated approximately 85% TPM1 knockdown using RNA interference; Ding’s expressly disclosed a specific mouse Tpm1 esiRNA reagent, MU-03366-1, associated with NM_024427 and multiple mouse Tpm1 transcript variants; Kittler taught that esiRNA regions were deliberately selected by DEQOR optimization to contain a high proportion of high-quality individual siRNAs and that selected target sequences were publicly retrievable; Ui-Tei supplied experimentally derived sequence criteria and computational methods for choosing highly effective individual mammalian siRNAs; and the resulting candidate siRNAs could be evaluated by routine gene-expression assays of the type actually employed in Ackerman.
Accordingly, selection of an individual high-quality TPM1 siRNA from an already identified TPM1 RNAi target sequence constituted no more than the use of a known siRNA-design technique for its established purpose. Eupheria materially narrows the sequence-selection issue. The skilled artisan was not merely presented with the entire Tpm1 transcript. The art had already selected a Tpm1 RNAi target region containing the exact 19-nucleotide core ultimately recited in the applicant’s SEQ ID NO. 21.
The obvious-to-try rationale (see MPEP § 2143) is applicable where the prior art provides a finite or readily traversable set of identified solutions and a skilled artisan has good reason to pursue those known options with a reasonable expectation of success. Here, the prior art first narrows the universe to TPM1, then to identified Tpm1 transcripts/optimized RNAi regions, and then provides published criteria for selecting the relatively short individual siRNA windows most likely to be effective.
The applicant has not established on the present record that the claimed duplexes possess any unexpected sequence-dependent TPM1 silencing property that distinguishes them from the class of rationally selected TPM1 RNAi reagents suggested by the prior art. Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to employ a rationally selected TPM1-directed siRNA in place of L3’s TPM1-neutralizing antibody.
L3 provides the explicit therapeutic objective, to inhibit TPM1 in order to ameliorate adverse retinal inflammatory, structural, and functional effects. Ackerman establishes that TPM1 is not merely a theoretical RNAi target, but is experimentally susceptible to approximately 85% knockdown by a sequence-specific RNAi reagent. Ding and Kittler establish that predesigned, computationally optimized esiRNA reagents directed specifically to Tpm1 and other mammalian targets were already available and that their target regions were selected to maximize production of effective individual siRNAs. Ui-Tei teaches how to choose an individual effective mammalian siRNA from such a target sequence. The proposed modification therefore retains L3’s biological target and merely substitutes one known TPM1-inhibition mechanism (i.e., sequence-specific RNA interference) for another TPM1 inhibitor. Such use of a known technique to address a known target where the technique predictably performs its established function is one of the rationales expressly recognized by KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-22 (2007) and MPEP § 2143.
A reasonable expectation of success does not require certainty or conclusive proof of therapeutic efficacy. Ackerman provides direct experimental evidence that a small panel of custom TPM1 RNAi sequences could be screened and that one produced approximately 85% TPM1 knockdown. Example 36 and Figure 52 therefore provide strong target-specific evidence that TPM1 is susceptible to RNAi-mediated suppression. Kittler teaches that DEQOR optimization increased the proportion of predicted high-quality siRNAs within an esiRNA target fragment and describes optimized esiRNA libraries having improved silencing efficacy (p. 337-338, Figure 1, and the discussion of DEQOR-optimized sequences). Ui-Tei independently teaches a high-success-rate methodology for selecting highly effective mammalian siRNAs from a known sequence. Accordingly, the skilled artisan would reasonably have expected that at least one rationally selected TPM1 siRNA from an optimized TPM1 target region would reduce TPM1 expression.
Taniguchi supplies the pharmaceutical-formulation and retinal-delivery portions of the instant claimed invention. Taniguchi teaches a pharmaceutical formulation in which lyophilized siRNA is dissolved in D-PBS and administered intravitreally. Taniguchi teaches that sequence-specific siRNAs can be effectively delivered to retinal tissue by intravitreal injection. A single intravitreal injection produced approximately 39-89% knockdown depending upon the retinal gene targeted, siRNAs directed against retinal cell-specific genes reduced expression by approximately 58-89%, and gene silencing was demonstrated across multiple retinal layers, including photoreceptor-associated regions. Taniguchi reports that injected siRNA rapidly diffused and penetrated throughout the retina, including to the RPE, and was biologically active in retinal ganglion cells, amacrine cells, and photoreceptors. Taniguchi further demonstrated protection against experimentally induced retinal ganglion-cell degeneration after sequence-specific siRNA-mediated gene knockdown (Abstract, Results section, “Quantitative assessment of efficiency of gene silencing by a single intravitreal injection of Accell siRNAs,” Figure 1).
Accordingly, once TPM1 was selected as the target and a TPM1-directed siRNA was selected using the teachings above, Taniguchi provides an express reason and a reasonable expectation for administering that sequence-specific RNAi reagent directly to retinal tissue. For these reasons, instant claim 1 would have been obvious.
Instant claim 5 further requires that the pharmaceutically acceptable addition comprise an excipient, stability additive, carrier, diluent, and/or solubilizer. Taniguchi, Methods, “Preparation of siRNA,” teaches that lyophilized Accell siRNA was reconstituted in Dulbecco’s phosphate-buffered saline (D-PBS) and adjusted to specified concentrations for intravitreal injection. D-PBS is therefore expressly employed as the aqueous vehicle/carrier or diluent for the siRNA pharmaceutical composition.
It would have been obvious to formulate the TPM1 siRNA suggested by the combined teachings in a physiologically acceptable aqueous carrier such as the D-PBS expressly taught by Taniguchi because Taniguchi uses that carrier for the same purpose of forming an injectable retinal siRNA composition. Accordingly, instant claim 5 is rejected as obvious.
Instant claim 6 requires delivery by intravitreal injection, subretinal injection, or suprachoroidal injection. The alternatives are disjunctive; therefore, the teaching of intravitreal injection is sufficient. Taniguchi, Abstract; Results, Figure 1; and Methods, expressly teaches administration of retinal siRNA by intravitreal injection. The Methods describe injection of 5 μL of siRNA solution into the vitreous body using a 32-gauge needle attached to a Hamilton syringe.
Because L3 identifies TPM1 as a retinal target, Ackerman establishes effective RNAi suppression of TPM1, and Taniguchi teaches successful intravitreal delivery of biologically active siRNAs throughout retinal tissue, it would have been obvious to administer the resulting TPM1-directed siRNA by intravitreal injection. Accordingly, instant claim 6 is rejected as obvious.
Instant claim 7 recites an immediate-release or controlled-release administration form. Taniguchi does not use the words “immediate release.” However, Methods, “Preparation of siRNA,” teaches siRNA directly dissolved in D-PBS, and the intravitreal procedure immediately administers that aqueous siRNA solution without an encapsulating depot, release-controlling polymer, implant, or other delayed-release structure. Under the broadest reasonable interpretation, Taniguchi’s directly injectable aqueous solution satisfies, or at minimum renders obvious, the claimed immediate-release alternative. Accordingly, instant claim 7 is rejected as obvious.
Instant claim 9 includes an injection form among its alternative administration forms. Taniguchi’s Methods, “Preparation of siRNA” prepares an aqueous siRNA solution specifically for ocular injection, and its intravitreal-injection procedure administers that solution through a needle and syringe. Thus, Taniguchi expressly teaches the claimed injection-form alternative.
It is noted, however, that claim 9 is separately rejected under 35 U.S.C. §112(b). For purposes of compact prosecution, the present prior-art rejection is made under the interpretation that “injection form” encompasses an injectable aqueous siRNA composition such as Taniguchi’s. Accordingly, instant claim 9 is rejected as obvious.
Instant claim 10 recites reducing neuroinflammation by administering the pharmaceutical composition of instant claim 1. L3 expressly establishes the relationship between TPM1 and retinal inflammatory signaling. L3’s Abstract reports TPM1-associated glial activation and inflammatory retinal changes, and section 2.7 attributes TPM1-mediated retinal effects to signaling involving FABP5/NF-κB.
Consequently, once the skilled artisan replaced L3’s antibody-mediated TPM1 inhibition with the effective RNAi-mediated TPM1 inhibition taught by Ackerman, Ding/Kittler and Ui-Tei, reduction of TPM1-associated retinal inflammatory activity would have been an expected consequence of successful inhibition of the same biological target. Taniguchi provides the means for delivering the resulting siRNA in biologically active form to retinal cells. Accordingly, instant claim 10 is rejected as obvious.
Instant claim 11 recites rescuing visual function by administering the composition of instant claim 1. L3 directly teaches improvement of retinal function resulting from TPM1 inhibition. In particular, section 2.5, entitled “Systemic administration of TPM1-specific neutralizing antibody counteracts age-related dendritic outgrowth and visual function decline in aged mice,” expressly reports functional retinal benefit from inhibition of TPM1. L3’s Abstract likewise reports that exogenous TPM1 accelerates retinal functional decline and that neutralizing TPM1 ameliorates retinal structural and functional changes.
Therefore, the claimed visual-function endpoint would have been reasonably expected from effective inhibition of the same TPM1 target using the RNA-interference approach taught by the additional references. Taniguchi additionally demonstrates that retinal siRNA knockdown can produce a biological neuroprotective effect, reporting significant prevention of NMDA-induced retinal ganglion cell death after Grin1 siRNA knockdown (Abstract). Accordingly, instant claim 11 is rejected as obvious.
The Examiner notes that currently accessible commercial Eupheria mouse product mTpm1, catalog MU-03366-1 as well as Sigma-Aldrich MISSION® esiRNA targeting mouse Tpm1 EMU033661 and human TPM1 esiRNA EHU081911 all target the instant claimed mRNA region. There is circumstantial evidence that the broader MISSION®/Eupheria platform long predates the instant application. Eupheria states that it was founded in 2010 around esiRNA technology, and Sigma's MISSION esiRNA specification discusses a product-distribution change beginning in late October/early November 2020, confirming that the commercial esiRNA platform itself was already operating then. These records provide additional corroboration concerning the relationship between the prior-art Tpm1 esiRNA resources and particular TPM1 target regions.
The current Sigma record for EMU033661 identifies the product as MISSION esiRNA “targeting mouse Tpm1,” associates it with NCBI NM_024427, and presently displays a cDNA target sequence containing ...GATCAGTAACCAAATTGGAGAAAAGCATTGATGACTTA..., which contains the DNA equivalents of the 19-nucleotide targeting portions of Applicant’s SEQ ID NO. 19 and SEQ ID NO. 21. The current Sigma record for EHU081911 identifies a human TPM1 MISSION esiRNA and presently displays a target region that contains the exact DNA-equivalent sequence GAAAAGCATTGATGACTTA, corresponding to the targeting portion of Applicant’s SEQ ID NO. 21. These current records are consistent with the dated 2015 Ding evidence that a specifically identified mouse Tpm1 esiRNA reagent, MU-03366-1, associated with NM_024427 and related Tpm1 transcripts, existed years before the applicant’s effective filing date.
However, because the presently located current product pages have not independently been shown to have publicly displayed those same target sequences prior to 21 May 2023, the examiner does not rely upon those current webpages for the proposition that the exact long target sequence itself was a §102(a)(1) printed publication before the effective filing date. These current webpages are not relied upon as the statutory prior-art basis for the rejection. Instead, the prima facie case rests upon the dated prior art comprising Li, Ackerman, Ding, Kittler, Ui-Tei, and Taniguchi, as outlined above.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 09 July 2026, have been fully considered.
The applicant argues that the amended claims are directed to specific synthetic siRNA molecules having defined nucleotide sequences rather than naturally occurring products and therefore are not directed to a judicial exception. The applicant further argues that the claimed invention constitutes a practical therapeutic application employing human-made molecules rather than a natural correlation.
The applicant argues that none of L3, Kieffer-Kwon, Bhattacharjee, Rashid, Santiago, or Irigoyen disclose or suggest the particular TPM1-targeting siRNA sequences now recited in amended claim 1 and that the prior art merely identifies TPM1 as a biological target rather than teaching the presently claimed therapeutic molecules. The applicant further argues that the examiner's previous proposed combination relied upon impermissible hindsight reconstruction because none of the cited references disclose the claimed sequences. These arguments have been fully considered, but they are not persuasive.
The examiner did not maintain that the identical nucleotide sequences now recited in amended claim 1 are expressly taught by the cited references. The amendment narrowing the TPM1 inhibitor to specific siRNA sequences does not overcome the § 103 rejection; rather, it merely shifts the obviousness inquiry from the genus of TPM1 inhibitors to the particular siRNA sequences, which are themselves obvious in view of the prior art. However, obviousness under 35 U.S.C. §103 does not require that the prior art expressly disclose the identical nucleotide sequence where the claimed sequence represents the predictable product of applying routine molecular biology techniques to a known therapeutic target.
L3 identifies TPM1 as a validated therapeutic target whose inhibition ameliorates retinal degeneration and preserves visual function. Kieffer-Kwon further teaches that RNA interference represents an effective mechanism for suppressing TPM1 expression. Together, these references would have motivated one of ordinary skill in the art to develop sequence-specific RNAi reagents directed against TPM1 for therapeutic use.
Design of effective siRNA molecules complementary to a known mRNA sequence was, at the time of the effective filing date, a routine and well-established methodology utilizing commercially available algorithms and conventional design rules. Numerous candidate siRNA molecules could be generated from the known TPM1 transcript with a reasonable expectation that at least some would effectively suppress TPM1 expression after routine empirical screening. The presently claimed siRNA sequences therefore represent species that would have been obtained through routine optimization after identification of TPM1 as the desired therapeutic target rather than through an unpredictable inventive process.
The applicant's argument that the cited references employ different therapeutic modalities (antibody inhibition, viral miRNAs, gene therapy, or delivery techniques) is not dispositive because obviousness may arise from substitution of one known inhibitory modality for another where both achieve the same biological objective. Selection of siRNA-mediated inhibition in place of antibody-mediated inhibition represents the predictable use of a known RNA interference technology to inhibit a validated molecular target.
The present rejection includes L3’s express teaching that TPM1 inhibition is therapeutically desirable in retinal tissue and combines that teaching with actual experimental TPM1 RNAi in Ackerman, the known nucleotide sequence of Tpm1, Ui-Tei’s objective rules for choosing highly active siRNA sequences, the specific preexisting Tpm1 esiRNA reagent disclosed by Ding, the optimized RNAi-region methodology of Kittler, the individual-siRNA selection methodology of Ui-Tei, and the retinal siRNA formulation and delivery teaching of Taniguchi providing experimental demonstration of intravitreal, sequence-specific retinal siRNA delivery and gene silencing.
Claim 5 is further rendered obvious by Taniguchi’s D-PBS siRNA formulation, claim 6 is further rendered obvious by Taniguchi’s intravitreal injection, and claim 7 is further rendered obvious by Taniguchi’s directly injectable aqueous siRNA solution under the broadest reasonable interpretation of immediate release. Claim 9 is further rendered obvious by Taniguchi’s injection-form embodiment, claim 10 is further rendered obvious by L3’s TPM1-associated inflammatory signaling, and claim 11 is further rendered obvious by L3’s direct demonstration that TPM1 inhibition ameliorates retinal functional decline. Consequently, the applicant’s observation that L3 itself does not disclose a TPM1 siRNA does not defeat the rejection. The combined teachings would have rendered the instant claims obvious to the person of ordinary skill at the time of the effective filing date of the instant invention.
The applicant’s assertion that the claimed sequences represent specifically developed molecules is also considered but is not, standing alone, evidence of nonobviousness. The relevant inquiry is whether the structural differences between the prior art and the claimed siRNAs would have been obvious. Here, the target transcript was known, RNAi against TPM1 had been demonstrated, and published sequence-selection criteria directing one of ordinary skill in the art toward candidates having the characteristics of the presently claimed duplexes.
No persuasive evidence of unexpected results specifically attributable to selecting SEQ ID NOS. 17/18, 19/20, or 21/22 over other rationally selected TPM1 siRNAs has been presented. If the applicant relies upon unexpected results, the evidence must establish a nexus to the feature alleged to distinguish the claims and must be commensurate in scope with the claims.
Conclusion
No claims are allowed.
The 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 (87 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.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights