DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response filed 04/02/2026 has been received and considered entered. This is a response to amendments and arguments filed 04/02/2026.
Election/Restrictions
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.
Claims Status
Claims 4-6, 8, 10, 14-16, 18-20, and 22-40 is/are cancelled. Claims 41-51 are newly added. Claims 1-3, 7, 9, 11-13, 17, 21, 41-51 is/are currently pending. Claims 1-3, 7, 9, 11-13, 17, 21, 41-51 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 § 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) 1-3, 7, 9, 11-13, 17, 21, 41-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO 2019217973 A1), as evidenced by Mahgoub (2020), Keenan (2015), Dewannieux (2003), and Kaneko (2011), and in view of GenBank: D84391.1 (2016), GenBank: AH002566.2 (2016), Nawrot (2006), Fakhr (2016), Kaneko (2011), and Zhao (2017). This is a new grounds of rejection necessitated by amendment.
Regarding claims 1, 7, 11, 17, 21, 49, 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”). Chen teaches that the siRNA targeting LINE-1 ORF2 may have the sequence of SEQ ID NO:95 (Table 2). Nucleotides 6-21 of SEQ ID NO:95 are 100% identical to nucleotides 1-16 of instant SEQ ID NO:48 (see alignment below).
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GenBank accession number D84391.1 is the Mus musculus (mouse) L1 repetitive element (LINE-1) gene reference sequence. Both Chen SEQ ID NO:95 and instant SEQ ID NO:48 are 100% identical to overlapping sequences within GenBank: D84391.1 (see alignments below), with the 3’ terminal nucleotide being the only mismatch between instant SEQ ID NO:48 and the GenBank reference sequence. Chen shows that siLine-1C (SEQ ID NO:95) effectively suppresses mouse Line-1 expression (Fig. 6A; page 16). It would have been obvious to an artisan to design siRNAs targeting the same region of the Line-1 coding sequence, and further obvious that siRNAs comprising significant target sequence overlap would be equivalent variants to the siLine1-1C of Chen. Furthermore, Fakhr teaches that siRNAs of lengths 19-25 nucleotides are equivalent in silencing efficiency (page 75). Nawrot teaches that up to four terminal (3’ or 5’) mismatches between an siRNA sequence and its corresponding target sequence are tolerated in mammals, and that the most potent siRNA are 19-bp long siRNA comprising 3’ TT overhangs or 3’ terminal mismatches (pages 915-916, Fig. 2). As such, siRNAs targeting a mouse Line1 target sequence overlapping that of siLine1-1C of Chen, having 19-25 nucleotides, and comprising up to four terminal (3’ or 5’) mismatches to the target sequence (encompassing instant SEQ ID NO:48) are rendered obvious by the combination of Chen, Fakhr, and GenBank D84391.1. Furthermore, based on the teachings of Nawrot, an artisan would be motivated to design an siRNA fitting these parameters, having 19 total nucleotides in the sense strand (instead of the 21 of Chen) and having a 1-2 nucleotide mismatch at the 3’ end of the sense strand (instead of the 100% sequence identity between the siRNA sense strand of Chen and the target sequence), as such an siRNA would exhibit greater silencing activity, thus being motivated to design siRNA encompassing instant SEQ ID NO: 48. Both Chen SEQ ID NO:95 and instant SEQ ID NO:48 are considered to be sense strands, as they are significantly identical to, but not complementary to, sequences within the target sequence (mouse Line-1).
Chen SEQ ID NO:95:
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Instant SEQ ID NO:48:
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Regarding claims 7, 17, 42, 44, 49-50, Chen teaches siRNA targeting mouse L1 ORF2-encoding sequences, and teaches that inhibitors of retrotransposition such as the siRNA targeting L1 ORF2-encoding sequences can be used to treat humans by administering these to humans (pages 2, 22). As the siRNA sequences taught by Chen specifically target mouse L1 ORF2-encoding sequences, it would have been obvious to an artisan that siRNA sequences specifically targeting human L1 ORF2-encoding sequences should be designed in order to enable the human therapeutic application described by Chen. Such siRNA design parameters are well known in the art and would be reasonably obvious for an artisan to implement to design siRNA targeting human L1 ORF2-encoding sequences instead of mouse L1 ORF2-encoding sequences (see Fakhr and Nawrot). Such a human L1 ORF2-encoding sequence would encompass that with GenBank accession number AH002566.2, an L1 ORF2-encoding reference sequence which encodes a protein sequence of instant SEQ ID NO:57 (see alignment below).
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Regarding claims 9, 45, and 51, 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, 12-13, 41, 43, and 46-48, 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, including any Alu DNA (single or double stranded) naturally produced by endogenously expressed LINE-1 ORF2. While the references do not teach that LINE-1 produces single-stranded Alu cDNA, as required by instant claims 41, 43, and 48, the single-stranded Alu cDNA of these claims is produced not by a method recited in the claims, but by a reverse transcription process naturally executed by endogenous proteins in the target cells (see instant claims 3, 13, 47, on which these claims depend, which recite that the siRNA reduces cytoplasmic accumulation of an Alu reverse transcription product, which product in turn is produced by LINE-1 ORF2, as described by Dewannieux).
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.
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). Kaneko teaches that conjugating siRNA with cholesterol allows the siRNA cell permeation, and in particular that this is applicable to RPE cells (page 9).
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, 17, and 49, Kaneko teaches that knockdown of Alu in human RPE cells blocks RPE degeneration (page 7).
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 04/02/2026 have been fully considered but they are not persuasive. Applicant argues that the new requirement that the siRNA comprises any one of SEQ ID NOs:47-49 and 51-54 overcomes the prior art because the art applied does not teach SEQ ID NOs:47-49 or 51-54. While siRNA of SEQ ID NO:47-49 and 51-54 were previously recited in the claims, this limitation was previously optional, whereas in the new amended claim listing, this limitation is now required. This new limitation has been addressed in the new grounds of rejection above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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