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 .
Election/Restrictions
Applicant’s election of the method of Group II, claims 11-18 and 20, in the reply filed on 15 October 2024 was acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election was treated as an election without traverse (MPEP § 818.01(a)). However, this restriction requirement has been withdrawn.
Applicant’s election without traverse of an inhibitory nucleic acid that targets an L1 ORF2 transcription product in the reply filed on 15 October 2024 was acknowledged. This election was considered FINAL.
Claim 17 further limits an embodiment of claim 16 that is not elected (the L1 ORF2 polypeptide that is targeted by the antibody of claim 16); however, this limitation does not exclude the inhibitory nucleic acid that was elected, as this nucleic acid targets an L1 ORF2 transcription product, which encodes an L1 ORF2 polypeptide. Therefore claim 17 was not withdrawn because it embraced an elected embodiment, but would be considered only to the extent that it read on that embodiment. If applicant amends claim 17 to read only on the specific limitation of claim 16 drawn to an antibody that is specific for an L1 ORF2 polypeptide, then claim 17 will be withdrawn as being drawn only to unelected species. Claim 18 limits one possible embodiment of claim 15 (the identity of the NNRTI) but is not limited to only that embodiment—in other words, claim 18 does not require that an NNRTI be used, only that if an NNRTI is used, that it be EFV or DLV. The requirements of claim 18 are fulfilled if an NNRTI is elected and the NNRTI is EFV or DLV, or when the RTase inhibitor used is not an NNRTI. Claim 18 was therefore not withdrawn, as it encompasses elected species of nucleic acid L1 ORF2 inhibitors. Election was made without traverse in the reply filed on 15 October 2024. If Applicant amends claim 18 to be drawn only to NNRTIs, then it will be withdrawn from consideration.
Claims Status
Claims 19 and 22-40 is/are cancelled. Claims 1-18 and 20-21 is/are currently pending. Claims 1-18 and 20-21 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 8-9, 11-16, 18, 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen (WO 2019217973 A1), as evidenced by Mahgoub (2020), Keenan (2015), Dewannieux (2003), and Kaneko (2011). This is a new rejection not necessitated by amendment.
MPEP §2131.01 provides guidance as to 35 U.S.C. 102 rejections over multiple references. Such rejection has been held to be proper when the extra references are cited to: (C) Show that a characteristic not disclosed in the reference is inherent.
The MPEP states: “To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill.” Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991) (The court went on to explain that “this modest flexibility in the rule that 'anticipation' requires that every element of the claims appear in a single reference accommodates situations in which the common knowledge of technologists is not recorded in the reference; that is, where technological facts are known to those in the field of the invention, albeit not known to judges.” 948 F.2d at 1268, 20 USPQ at 1749-50.). Note that the critical date of extrinsic evidence showing a universal fact need not antedate the filing date. See MPEP §2124.
Regarding claims 1, 11, and 21, Chen teaches the administration to a subject cell an inhibitor of reverse transcriptase activity (an siRNA targeting LINE-1 ORF2) (Figure 1D). Chen teaches that the subject has osteoarthritis (page 60, “In order to reduce the severity of and/or prevent [osteoarthritis], feasible methods to suppress Line-1 including administration of…siRNA against Line-1 are useful as therapeutic approaches in counteracting osteoarthritis”).
Regarding claims 4 and 14, Chen teaches that the inhibitor of RTase activity is an inhibitor of L1 (also known as LINE-1) ORF2 activity (Figure 1D; page 60).
Regarding claims 5, 8, 15, and 18, Chen teaches that the inhibitor of RTase activity is an L1 ORF2 inhibitor (Figure 1D; page 60).
Regarding claims 6 and 16, Chen teaches that the L1 ORF2 inhibitor is an inhibitory nucleic acid that targets L1 ORF2 mRNA (an siRNA targeting L1 ORF2) (Figure 1D; page 60).
Regarding claim 9, Chen teaches that the L1 ORF2 inhibitor is administered through oral or intravenous administration (pages 61-62).
Chen does not teach that the administration of an inhibitor of reverse transcriptase activity comprises part of a method for protecting RPE cells, photoreceptor cells, or choroidal cells (required for claims 11-18 and 20) or for treating age-related macular degeneration or geographic atrophy of the eye (required by claims 1-10 and 21); however, protection of RPE cells, photoreceptor cells, or choroidal cells, and treatment of age-related macular degeneration or geographic atrophy of the eye are considered to be inherent properties of the methods taught by Chen, resulting from the inherent properties of the siRNA of Chen and the association between osteoarthritis and age-related macular degeneration.
Mahgoub teaches that osteoarthritis and age-related macular degeneration (AMD) (including global atrophy, considered an advanced stage of AMD, page 37) are comorbid diseases, with 20.7% of osteoarthritis patients in the study being diagnosed with AMD (page 37), compared to 7.4-12.3% incidence of AMD in healthy populations, and evidence that AMD and osteoarthritis incidence are related (page 36). Mahgoub further teaches that severity of AMD and severity of osteoarthritis are positively correlated (pages 37-39; Table 2; Fig. 2). Keenan teaches a positive association between AMD and osteoarthritis diagnoses (see abstract; page 2616, “our findings suggest that people with [osteoarthritis] are at modestly but significantly higher risk of AMD”). In a method of treating osteoarthritis in a patient having osteoarthritis, said patient would therefore have a significantly increased probability of having comorbid AMD relative to the population of patients without osteoarthritis. As such, approximately one-fifth of patients administered the siRNA of Chen would have both osteoarthritis and AMD, and one-tenth of said patients having both osteoarthritis and AMD would have AMD progressed to geographic atrophy (page 37 of Mahgoub). As the siRNA would treat or prevent both osteoarthritis, as claimed in Chen, and additionally AMD and geographic atrophy of the eye by the nature of the inherent properties of the siRNA, the administration of the claimed siRNA of Chen to patients with osteoarthritis and comorbid AMD and/or geographic atrophy constitutes a method of treating osteoarthritis and AMD and geographic atrophy.
Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and propagation of Alu, while Kaneko teaches that inhibition of Alu prevents degradation of retinal cells in macular degeneration.
Regarding claims 1 and 11, Dewannieux teaches that the LINE-1 ORF2 protein associates with and reverse transcribes Alu RNA, and is crucial in promoting its propagation (abstract; Figure 7).
Regarding claims 2-3 and 12-13, Dewannieux teaches that LINE-1 ORF2 protein associates with Alu at the ribosome (Figure 7). As ribosomes are cytoplasmic structures, the inhibition of ORF2 would reduce the quantity of Alu reverse transcribed in the cytoplasm.
Regarding claims 1 and 11, Kaneko teaches that inhibition or degradation of Alu prevents degradation of retinal pigmented epithelium cells in macular degeneration (abstract; pages 5-7).
Regarding claims 3 and 13, Kaneko teaches that knockdown of DICER1, which degrades Alu, results in accumulation of Alu RNA in the cytoplasm (page 5).
Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and transposition of Alu. Kaneko teaches that in human RPE cells, Alu accumulation is causative of degradation of RPE cells, and that inhibition of Alu accumulation prevents such degradation of RPE cells. Given that Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and transposition of Alu, and decreased rates of transposition would naturally result in fewer genomic repeats of Alu and thus fewer opportunities for Alu RNA expression and lower Alu RNA expression, the administration of the siRNA of Chen to patients, as in Chen, by inhibiting LINE-1 ORF2 activity would inherently result in a decrease in Alu accumulation or expression, thereby protecting RPE cells from degradation and treating macular degeneration and geographic atrophy.
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) 1-18 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO 2019217973 A1), in view of Kaneko (2011), and Zhao (2017), as evidenced by Mahgoub (2020), Keenan (2015), Dewannieux (2003), and Kaneko (2011). This is a new rejection not necessitated by amendment.
Regarding claims 1, 11, and 21, Chen teaches the administration to a subject cell an inhibitor of reverse transcriptase activity (an siRNA targeting LINE-1 ORF2) (Figure 1D). Chen teaches that the subject has osteoarthritis (page 60, “In order to reduce the severity of and/or prevent [osteoarthritis], feasible methods to suppress Line-1 including administration of…siRNA against Line-1 are useful as therapeutic approaches in counteracting osteoarthritis”).
Regarding claims 4 and 14, Chen teaches that the inhibitor of RTase activity is an inhibitor of L1 (also known as LINE-1) ORF2 activity (Figure 1D; page 60).
Regarding claims 5, 8, 15, and 18, Chen teaches that the inhibitor of RTase activity is an L1 ORF2 inhibitor (Figure 1D; page 60).
Regarding claims 6, 7, 16, and 17, Chen teaches that the L1 ORF2 inhibitor is an inhibitory nucleic acid that targets L1 ORF2 mRNA (an siRNA targeting L1 ORF2) (Figure 1D; page 60).
Regarding claim 9, Chen teaches that the L1 ORF2 inhibitor is administered through oral or intravenous administration (pages 61-62).
Regarding claims 10 and 20, Chen teaches that the reverse transcription inhibitor is an L1 ORF2-targeting siRNA (Figure 1D).
However, Chen does not teach that the administration of an inhibitor of reverse transcriptase activity comprises part of a method for protecting RPE cells, photoreceptor cells, or choroidal cells (required for claims 11-18 and 20) or for treating age-related macular degeneration or geographic atrophy of the eye (required by claims 1-10 and 21), nor does Chen teach that the inhibitor’s target is human L1 ORF2 (required for claim 17).
Mahgoub teaches that osteoarthritis and age-related macular degeneration (AMD) (including global atrophy, considered an advanced stage of AMD, page 37) are comorbid diseases, with 20.7% of osteoarthritis patients in the study being diagnosed with AMD (page 37), compared to 7.4-12.3% incidence of AMD in healthy populations, and evidence that AMD and osteoarthritis incidence are related (page 36). Mahgoub further teaches that severity of AMD and severity of osteoarthritis are positively correlated (pages 37-39; Table 2; Fig. 2). Keenan teaches a positive association between AMD and osteoarthritis diagnoses (see abstract; page 2616, “our findings suggest that people with [osteoarthritis] are at modestly but significantly higher risk of AMD”). In a method of treating osteoarthritis in a patient having osteoarthritis, said patient would therefore have a significantly increased probability of having comorbid AMD relative to the population of patients without osteoarthritis. As such, approximately one-fifth of patients administered the siRNA of Chen would have both osteoarthritis and AMD, and one-tenth of said patients having both osteoarthritis and AMD would have AMD progressed to geographic atrophy (page 37 of Mahgoub). As the siRNA would treat or prevent both osteoarthritis, as claimed in Chen, and additionally AMD and geographic atrophy of the eye by the nature of the inherent properties of the siRNA, the administration of the claimed siRNA of Chen to patients with osteoarthritis and comorbid AMD and/or geographic atrophy constitutes a method of treating osteoarthritis and AMD and geographic atrophy. Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and propagation of Alu, while Kaneko teaches that inhibition of Alu prevents degradation of retinal cells in macular degeneration.
Regarding claims 1 and 11, Dewannieux teaches that the LINE-1 ORF2 protein associates with and reverse transcribes Alu RNA, and is crucial in promoting its propagation (abstract; Figure 7).
Regarding claims 2-3 and 12-13, Dewannieux teaches that LINE-1 ORF2 protein associates with Alu at the ribosome (Figure 7). As ribosomes are cytoplasmic structures, the inhibition of ORF2 would reduce the quantity of Alu reverse transcribed in the cytoplasm.
Regarding claims 1 and 11, Kaneko teaches that inhibition or degradation of Alu prevents degradation of retinal pigmented epithelium cells in macular degeneration (abstract; pages 5-7).
Regarding claims 3 and 13, Kaneko teaches that knockdown of DICER1, which degrades Alu, results in accumulation of Alu RNA in the cytoplasm (page 5).
Regarding claims 7 and 17, Kaneko teaches that knockdown of Alu in human RPE cells blocks RPE degeneration (page 7).
Regarding claims 10 and 20, Kaneko teaches that conjugating siRNA with cholesterol allows the siRNA cell permeation, and in particular that this is applicable to RPE cells (page 9).
Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and transposition of Alu. Kaneko teaches that in human RPE cells, Alu accumulation is causative of degradation of RPE cells, and that inhibition of Alu accumulation prevents such degradation of RPE cells. Given that Dewannieux teaches that LINE-1 ORF2 is crucial for the reverse transcription and transposition of Alu, and decreased rates of transposition would naturally result in fewer genomic repeats of Alu and thus fewer opportunities for Alu RNA expression and lower Alu RNA expression, the administration of the siRNA of Chen to patients, as in Chen, by inhibiting LINE-1 ORF2 activity would inherently result in a decrease in Alu accumulation or expression, thereby protecting RPE cells from degradation.
As Kaneko teaches a method for protecting human RPE cells from degradation by administering to RPE cells siRNA targeting Alu in order to decrease expression or accumulation of Alu, and it was known in the art that inhibition of LINE-1 ORF2 activity or expression would likewise decrease expression or accumulation of Alu, as discussed above, it would have been obvious to a person of ordinary skill in the art at the time of filing that the LINE-1 ORF2 reverse transcriptase inhibitory siRNA of Chen could be used instead of the siRNA targeting Alu RNA of Kaneko, as an obvious variant, in order to reduce accumulation of Alu RNA in human RPE cells, and furthermore, that the siRNA should be designed to target human LINE-1 ORF2 instead of mouse LINE-1 ORF2. Additionally, as LINE-1 ORF2 has cellular targets aside from and in addition to Alu RNA, the inhibition of LINE-1 ORF2, as in Chen, instead of only Alu, as in Kaneko, would result in downregulation of additional desired nucleic acids and proteins (Chen Figures 1D-1I; see Zhao, genes such as ADAMTS5, which are also downregulated by siRNA targeting ORF2, are implicated in age-related macular degeneration), and it would thus be additionally obvious to a skilled artisan to substitute the siRNA targeting only Alu of Kaneko with the siRNA targeting LINE-1 ORF2 of Chen. Furthermore, as Kaneko teaches that cholesterol conjugation of siRNA allows for RPE cell permeation of the siRNA, it would have been obvious to a person of ordinary skill in the art at the time of filing that siRNA of Chen to be administered to RPE cells, as in Kaneko, should be conjugated to cholesterol in order for the siRNA to be introduced into the cell cytoplasm.
Response to Arguments
Applicant's arguments filed 08/26/2025 have been fully considered but they are not persuasive.
Applicant argues on pages 8-9 of the filed arguments that Chen does not suggest that NRTIs would treat macular degeneration, and that thus there would be no motivation to target RPE cells for delivery of NRTIs. However, claims 11-18 and 20 are not drawn to a method of treating macular degeneration. Claims are not drawn to any method treating a disease, they only recite a method of protecting RPE, choroidal cell or photoreceptor cells. Once a compound is delivered to a subject as taught in Chen, the compound will produce inhibitory effects in all the cells of the subject, not just in the intended organ or cells. Furthermore, the properties of LINE-1 ORF2 and Alu taught by Kaneko and Dewannieux would render obvious that by administering an siRNA targeting LINE-1 ORF2 as in the methods of Chen, protection of RPE cells would result as a natural consequence. The siRNA of Chen would knock down LINE-1 ORF2 expression in any cell to which it is introduced, resulting in global (i.e., nuclear and cytoplasmic) abolishment or reduction of LINE-1 ORF2 activity. While it may not have been recognized at the time of filing that cytoplasmic activity, and not nuclear activity, of LINE-1 ORF2 was crucial for Alu reverse transcription, as additionally argued by the applicant, it was known that LINE-1 ORF2 activity was crucial for Alu reverse transcription, as discussed above. As an siRNA targeting LINE-1 ORF2 would globally knock down LINE-1 ORF2 expression by preventing translation, an artisan would find obvious that administering an siRNA targeting LINE-1 ORF2, such as those taught by Chen, would reduce Alu reverse transcription, regardless of whether this reverse transcription occurred in the nucleus or cytoplasm. As such, modifications of the siRNA of Chen to facilitate delivery to RPE cells would additionally be obvious to an artisan at the time of filing.
The Examiner recognizes the applicant’s argument and evidence that one NRTI which inhibits LINE-1 ORF2 activity was known to inhibit LINE-1 ORF2 activity in the nucleus, not the cytoplasm, and was known to cause and not prevent damage to RPE cells. As a result, it would not be obvious to an artisan that any NRTI could be used to protect RPE cells or inhibit cytoplasmic Alu reverse transcription. Notably, however, the NRTI described in the provided art as damaging RPEs or acting in the nucleus and not the cytoplasm is a small molecule drug and not an inhibitory RNA. The mechanisms of action of RNAi-associated inhibitory RNAs, such as siRNAs, and small molecules such as dideoxyinosine are markedly different. Dideoxyinosine acts directly upon the LINE-1 ORF2 protein to inhibit activity, while an siRNA targeting the mRNA encoding LINE-1 ORF2 prevents the synthesis of the protein itself, thus inhibiting LINE-1 ORF2 activity globally, in the cytoplasm and the nucleus. Furthermore, while dideoxyinosine damages RPE cells, Kaneko teaches siRNA administered to RPE cells which do not damage RPE cells, as discussed in the rejection above. Given the significant difference in structure and function of dideoxyinosine and siRNAs, and the evidence provided in Kaneko regarding the safety of siRNAs administered to RPE cells, an artisan would assume that an siRNA targeting LINE-1 ORF2 would not damage RPE cells. As such, the evidence provided regarding the lack of cytoplasmic activity of an NRTI and the damage done by an NRTI to RPE cells does not render non-obvious the use of siRNAs to knock down L1 ORF2.
Furthermore, while the applicants argue that it was not known that LINE-1 ORF2 reverse-transcribed Alu in the cytoplasm, Dewannieux, as discussed in the rejection above, does teach that LINE-1 ORF2 associates with and reverse-transcribes Alu at the ribosome (which is in the cytoplasm). It therefore would have been obvious to an artisan that in order to reduce Alu reverse transcription by targeting LINE-1 ORF2 activity, cytoplasmic activity of LINE-1 ORF2 would need to be targeted.
For the reasons detailed above, the rejections of claims 11-18 and 20 under 35 USC 103 are maintained.
Conclusion
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635