DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 08/18/2026 has been entered.
Applicants’ arguments and amendments to the claims filed on August 18, 2026, have been received and entered. Claims 14, 16, 17 and 25 and 27 have been amended, while claims 13, 19-21, 23-24 and 27 have been canceled.
. Claims 1-12, 14-18, 22, 25 and 26 are pending in the instant application.
Election/Restrictions
Applicants’ election without traverse of claims 14-18, 22, 25-26 and 27 (group III) in the reply filed on September 9, 2025, was acknowledged. Applicant further elects the following species: (i) the RPE-specific promoter sequence of Best! (SEQ ID NO: 7); (ii) wild-type Db13 polypeptide (SEQ ID NO: 1); and (iii) wild-type Db13 nucleotide sequence (SEQ ID NO: 3).
Claims 1-12 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 9, 2025.
Priority
This application is a 371 of PCT/GB2021/050402 filed on 02/18/2021, which claims priority from foreign application number 2002202.6 filed in UK on 02/18/2020.
Claims 14-18, 22, 25 and 26 are under consideration.
New & Maintained -Claim Rejections - 35 USC § 112- in modified form
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 14-18, 22, 25 and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating retinal degeneration that is caused by defective phagocytosis of photoreceptor outer segments in a subject, said method comprising administering to the subject, an effective amount of AAV-2 or AAV-8 vector comprising a promoter operably linked to a nucleotide sequence comprising SEQ ID NO: 3 or 4 encoding a Dbl3 polypeptide, wherein said administration results in increased phagocytosis of photoreceptor outer segment in said subject, and wherein said administering is a direct retinal, subretinal or intravitreal injection, thereby treating retinal degeneration in the subject, does not reasonably provide enablement for treating all the retinal dysfunction and/or degeneration of distinct etiology and pathology, preventing one or more of the following phenotypes associated with phagocytosis-related retinal degeneration as set forth in claim 16, or delivering a nucleic acid variant encoding functional Dbl3 or delivering a phosphomimetic to treat any other condition as broadly encompassed by the claim. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The claims are directed to a method of treating any retinal dysfunction and/or degeneration comprising administering to a subject, an adeno associated virus (AAV) vector comprising an expression construct comprising a promoter operably linked to a nucleic acid sequence of SEQ ID NO: 4, a nucleic acid sequence of SEQ ID NO: 3, or a nucleic acid sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 3 that encodes a functional Dbl3 polypeptide, wherein the promoter is an RPE- specific promoter, wherein the AAV vector capsid is derived from AAV2 or AAV8, and wherein the route of administration is direct retinal, subretinal or intravitreal injection. The, claims as written encompasses treating a broad genus of retinal dysfunction and/or degeneration of distinct etiology and pathology by delivering a nucleic acid variant of Dbl3 and delivering a nucleic acid sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 3 or a sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 1. Dependent claims limit the retinal dysfunction and/or degeneration is an inherited retinal disorder or dystrophy, such as retinitis pigmentosa or macular degeneration; optionally wherein the macular degeneration is age-related macular degeneration (AMD), such as wet or neovascular AMD or geographic atrophy, or inherited dystrophies such as Stargardt and Sorsby diseases
Breadth of the claims:
The claims are broadly directed treating retinal dysfunction and/or degeneration of any etiology and pathology comprising administering AAV2 or AAV8 encoding any Dbl3 polypeptide. Dependent claims limit retinal dysfunction and/or degeneration is an inherited retinal disorder or dystrophy, such as retinitis pigmentosa or macular degeneration; optionally wherein the macular degeneration is age-related macular degeneration (AMD), such as wet or neovascular AMD or geographic atrophy, or inherited dystrophies such as Stargardt and Sorsby diseases. For purposes to be shown in the state of prior art, the question of lack of enablement is discussed.
Guidance of the Specification and The Existence of Working Examples:
The specification teaches expression of Dbl3 and Db13 Y570D can rescue loss of vision in an animal model of retinitis pigmentosa, RCS rats. The RCS rat is a well- established model of inherited loss of vision due to a lack of phagocytosis caused by inactivating mutations in the MerTK gene. Retinal degeneration starting within the first weeks after birth shows as a progressive loss of photoreceptors resulting in thinning of the outer nuclear layer (ONL) and defects in the retinal outer limiting membrane (OLM). First, Dbl3 was delivered by subretinal injection of AAV-8 particles, which leads to preferential transduction of the RPE, for expression by a CMV promoter (CMV-DbI3) and compared to a vector leading to re-expression of MerTK (CMV-MerTK). Both CMV-Db13 and CMV- MerTK vectors attenuated loss of retinal function as determined by increased b-wave amplitudes in ERGs comparing to PBS injected control at 6 weeks after injection (Fig. 18A,B). Expression of Db13 rescued retinal function as did the expression of MerTK. Analysis of retinal tissue sections using confocal laser scanning microscopy revealed that ) retinal integrity was greater in both Dbl3 and MerTK transduced RPE when compared to PBS injected retinas, as determined by the thickness of the ONL. The integrity of OLM was also noticeable in CMV-Dbl3 compared to PBS injected control where it is highly degenerated (Fig. 19A-B, E). Next, vectors were generated that make use of an RPE-specific promoter. A Best promoter fragment (SEQ. ID NO:7) was cloned into AAV vectors along with either Db13 (SEQ ID NO: 3) or DbI3 Y570D (SEQ ID NO: 4). Best1-Db13 or Best1-Db13 YS70D AAV vectors were injected subretinally in RCS eyes and retinal function was analyzed after 6 weeks or 12 weeks. Both Best-Dbl3 and Best1-Db13 Y570D vectors rescued retinal function and attenuated loss of vision in RCS rats 6 weeks after AAV injection, as shown by the increased b-wave amplitudes recorded in Best-Dbl3 and Best1-Dbl3 Y570D AAV injected RCS eyes comparing to PBS injected controls (Fig. 18A,C). Improved retinal function was also maintained at 12 weeks after injection of either Best-Dbl3 or Best1- DbI13 Y570D AAV vectors (Fig. 18D). The observed values of b-wave amplitudes after injection of Best1-Dbl3 or Best1-Db13 Y570D particles were as high or higher than what has previously been reported for AAV-mediated expression of MerTK itself using an RPE- specific promoter and similar experimental strategy and methodology (Smith et al., 2003). Thus, expression of Db13 and Db13 Y570D can efficiently rescue retinal function even when the defect is caused by mutations in a different gene. Analysis of retinal tissue using confocal laser scanning microscopy indicated that at 12 weeks after injection, retinal degeneration was strongly attenuated in eyes injected with an AAV vector encoding either Dbl3 or Db13 Y470D under the control of Best] promoter, as shown by the greater ONL thickness and presence of OLM in the RPE (Fig. 19C, D, E). Overall, these results demonstrate that expression of Db13 or the constitutively active phosphomimetic Db13 Y470D mutant polypeptide driven by an RPE specific promoter can efficiently prevent or reduce retinal degeneration and loss of retinal function and integrity associated with a defect in phagocytosis.
State of the Art and Predictability of the Art and Amount of Experimentation Necessary:
Claims 14, 18, 22, 25 and 26 are directed to a method of treating retinal dysfunction and/or degeneration by administering to a subject: an adeno associated virus-2 or 8 (AAV) vector comprising an expression construct comprising a promoter operably linked to a nucleic acid sequence of SEQ ID NO: 4, a nucleic acid sequence of SEQ ID NO: 3, or a nucleic acid sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 3 that encodes encoding a functional Dbl3 polypeptide. It is relevant to note that independent claim as such does not even require expression of functional Dbl1 polypeptide in RPE cells to have nay biological effect. The claims broadly encompass treating any retinal dysfunction and/or degeneration. The guidance provided in the specification is limited to an animal model of retinitis pigmentosa, RCS rats (see above). The state of the art teaches RCS rat has been extensively used in the past as an animal model to study retinal degeneration. However, study disclosed by Gias reported rat model fails to reach a normal cortical response level to pattern stimulation or luminance changes, with normal development compromised before maturity is attained (see page Gias et al Vision Research 51 (2011) 2176–2185, page 2184, col. 1, last para.). The use of RCS rat as exemplified in the instant application harbors a mutation in the Mertk gene, which is mostly focused on anatomical and functional changes, such as photoreceptor death associated with the Mertk mutation in retinal pigment epithelium (RPE). Although the RCS rat model is widely used and provides valuable insights into retinal degeneration, it is essential to acknowledge that animal models may not fully recapitulate the complexity of human retinal diseases. Differences in genetic background, physiological factors, and disease progression patterns can influence the translatability of findings to human conditions (Ahluwalia et al Int. J. Mol. Sci. 2024, 25(7), 3749) .
The art teaches that there are two forms of AMD depending on how the macula is damaged, dry AMD and wet or neovascular AMD. Dry AMD is the most common form; waste materials accumulate under the retina as old cells die, not being replaced. Wet AMD is less common but can lead to vision loss much more quickly. Wet AMD is characterized by new abnormal blood vessels developing under the macula, where they do not normally grow (see abstract, Marchesi et al Int. J. Mol. Sci. 2024, 25, 13053. 1-30, IDS). The specification provides no guidance on treating wet AMD or Stargardt's macular retinal degeneration. Ghosh teaches that the RPE cells have a major role in the development of dry age-related macular degeneration (AMD) (emphasis added). Ghosh present evidence that βA3/A1-crystallin, encoded by the Cryba1 gene, a protein known to be important for lysosomal clearance in the RPE and also has a role in epithelial-to-mesenchymal transition (EMT) of RPE cells (present in eye) (see Ghosh et al Invest Ophthalmol Vis Sci. 2018; 59(4), 1-13, IDS). Therefore, the results exemplified in the instant specification is limited to direct subretinal injection of Best1-Db13 YS70D AAV8 vectors or Best1-Db13 AAV8 vectors showing efficient infection that could not be extrapolated to treatment of wet AMD or any other neurodegenerative disease encompassed by the claims. The claims require administering a nucleic acid encoding Dbl3 polypeptide comprises the sequence of SEQ ID NO: 1, or a sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 1 that maintains the function of the Dbl3 polypeptide. Claims further limit the Dbl3 polypeptide is a phosphomimetic; optionally wherein a) the phosphomimetic mimics phosphorylation of the conserved TERVYVREL activation motif. Thus, polypeptide comprises the amino acid sequence of phosphomimetic mimics phosphorylation of the conserved TERVYVREL activation motif or a nucleic acid sequence with at least 90% sequence identity to the sequence of SEQ ID NO: 3. However, the art teaches mutating any amino acid residue or type of amino acid substitution is critical for the resulting outcome. The art teaches phosphomimetic amino acid substitutions like aspartic acid (Asp) or glutamic acid (Glu) are useful for approximating the effect of phosphorylation, they are not a perfect replacement for the actual, transient post-translational modification. (see Kozeleková et al Frontiers in Chemistry, 2022, 10, 1-17, IDS). Further, Ron (EMBO J. 7 (8), 2465-2473, 1988) reported overexpressing a nucleotide sequence encoding Dbl3 having 91.8% identity to SEQ ID NO:3 (see sequence search alignment) is sufficient to transform NIH/3T3 cells, but specific structural alterations of its coding region significantly enhance its transforming activity (abstract). The guidance provided in the specification is limited to Best1-Db13 YS70D (SEQ ID NO: 4)- AAV8. One of ordinary skill in the art would have to perform undue experimentation to make and use the invention for the broad genus of Dbl3 polypeptide, without reasonable expectation of success. Although, specific vectors, promoters, nucleic acid encoding a Dbl3 polypeptide, and route of administration might be or may have been effective for rescuing phagocytosis of photoreceptor outer segment. Gene therapy as a broad-based art is clearly unpredictable in terms of achieving levels and duration of expression of a gene of interest, which results in a therapeutic effect. Given that RCS model signifies a very specific, local mechanism of disease that does not extrapolate to the vast genetic and cellular heterogeneity of human retinal dysfunction and/or degeneration as broadly embraced by the breadth of the claim. This clearly establishes the unpredictability of the animal models currently being used for evaluating gene delivery to treat and/or prevent any other retinal dysfunction and/or degeneration other than retinal dysfunction and/or degeneration caused by defective phagocytosis of photoreceptor outer segments. An artisan would have to perform undue experimentation to make and use the invention without reasonable expectation of success.
Response to arguments
Applicant argues that the claims are limited to specific route of delivery and type of vector and therefore based on the teachings in the current specification, combined with the knowledge in the art (at the relevant filing date), one of ordinary skill in the art at the time of invention could have used the claimed methods without undue experimentation. Applicants’ arguments have been fully considered but are not found persuasive.
Applicants’ amendment of base claim 14 to recite specific route of administration and limiting the scope of AAV vector, only in part obviates the grounds for rejection. It is indicated that the disclosure is not enabled for treating a broad genus of any retinal dysfunction and/or degeneration other than those caused by defective phagocytosis of photoreceptor outer segments by direct deliver of Db13 (SEQ ID NO: 3) or DbI3 Y570D (SEQ ID NO: 4) into the retina of the subject for the reasons discussed above.
Withdrawn- Claim Rejections - 35 USC § 103-in modified form
Claims 14-18, 22, 25-26 and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over LaVail et al (Adv Exp Med Biol 2016,.854:487–493IDS) as evidenced by Heynen et al (PLoS One, 2013, e53806, 1-13), Zihni et al (Journal of Cell Biology, 2014 11-127, IDS)/Zihni et al (2, Nature Cell Biology, 2017, 19, 1049-1060, IDS), and Bare (US20090270332, 10/29/2009). Upon further consideration, previous rejection of claims is hereby withdrawn in view of new rejection presented below.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 14-18, 22, 25and 26 remain rejected under 35 U.S.C. 103 as being unpatentable over LaVail et al (Adv Exp Med Biol 2016,.854:487–493IDS) as evidenced by Mahajan (JBC, 2003, 42596–42603), Heynen et al (PLoS One, 2013, e53806, 1-13), Zihni et al (Journal of Cell Biology, 2014 11-127, IDS)/Zihni et al (2, Nature Cell Biology, 2017, 19, 1049-1060, IDS), and Bare (US20090270332, 10/29/2009).
With respect to claims 14-17, 25, LaVail teaches a method of treating retinal degeneration, said method comprising subretinal injections of the AAV2 vector encoding a gene product (hMERTK) under the control of VMD2-promoter (RPE cell specific promoter) in a RCS rats with inherited retinal dystrophy due to a deletion in the Mertk gene or Mertk knockout mice (see page 65.2.2, page 489). It is disclosed that retinal dysfunction and/or degeneration is characterized by defective phagocytosis of photoreceptor outer segments that is reversed in RCS rat and KO mouse following treatment with AAV2-VMD2-hMERTK (see 65.3.1, page 489, last para. fig. 65.1 and fig. 65.2d). It is disclosed that the extent of photoreceptor rescue typically was most of the full retinal length, as viewed in a retinal spidergram of ONL thickness (Fig. 65.2c). The ERG responses were dramatically different for each of the waveforms; the uninjected eyes showed no scotopic a- or b-waves, and only minimal photopic b-waves, but the vector-injected eyes had responses that were 40–60 % of normal (Fig. 65.2d). Mahajan provides evidence that MerTK facilitated the phosphorylation of Vav1, a guanine nucleotide-exchange factor (GEF), which activates Rac1, Cdc42, and RhoA (abstract).
Regarding claim 22, teaches phagocytosis in outer segment in increased in RCS rats and Mertk KO mouse thereby rescuing phagocytosis of photoreceptor outer segments (see page 489, para. 1, page 490, para. 1, fig.).
LaVail differs from claimed invention by not disclosing AAVt encoding a gene product is Dbl3 polypeptide.
Heynen reported that the functional CDC42 is important for correct tissue organization already during retinal development. Its absence leads to severe destabilization of the postnatal retina with strong degeneration and loss of retinal function (abstract). It is disclosed that absence of CDC42 during development caused improper retinal lamination, and resulted in progressive retinal degeneration, loss of function and vascular disorganization (see page 2, col. 1, para.1). The combination of reference differs from claimed invention by not disclosing activating CDC42 in the retina of a subject in need thereof to treat progressive retinal degeneration.
Zihni cure the deficiency by disclosing the use of nucleic acid encoding Dbl3 that functions as a GEF that stimulates spatially restricted activation of Cdc42 at apical cell–cell contacts (see page 116, col. 2, para. 2). Zihni teaches an expression construct comprising a promoter operably linked to a nucleic acid sequence encoding a DbI3 polypeptide (see page 124, col. 2, last para.). This is further supported by Zihni (2) who teaches overexpressing Dbl3 activates apical Cdc42 and thereby stimulates two effector mechanisms: induction of apical MLC phosphorylation by MRCK and aPKC-stimulated downregulation of junctional RhoA-dependent actomyosin contractility. Dbl3 signaling hence leads to a shift in the actomyosin activity gradient to stimulate apical polarization (Fig. 6h). These results further indicate distinct roles for RhoA_ROCK and Cdc42-MRCK signaling in epithelia (see page 1055, col. 1, para. 1) . Zihni (2) teaches an expression construct comprising a promoter operably linked to a nucleic acid sequence encoding a DbI3 polypeptide (see under methods).
Bare provides the relevant sequence information of nucleic acid and Dbl3 polypeptide as set forth in SEQ ID No 195 that has 100% sequence identity to SEQ ID NO: 1, 2 (see sequence search results) (limitation of claims 18, 26). Bare further discloses nucleic acid as set forth in SEQ ID NO: 70 that has 99% sequence identity to SEQ ID NO: 3 (see sequence search results) .
Query Match 100.0%; Score 5120; Length 985;
Best Local Similarity 100.0%;
Matches 985; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MQDIAFLSGGRGKDNAWIITFPENCNFRCIPEEVIAKVLTYLTSIARQNGSDSRFTIILD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MQDIAFLSGGRGKDNAWIITFPENCNFRCIPEEVIAKVLTYLTSIARQNGSDSRFTIILD 60
Qy 61 RRLDTWSSLKISLQKISASFPGNLHLVLVLRPTSFLQRTFTDIGFWFSQEDFMLKLPVVM 120 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RRLDTWSSLKISLQKISASFPGNLHLVLVLRPTSFLQRTFTDIGFWFSQEDFMLKLPVVM 120
Qy 121 LSSVSDLLTYIDDKQLTPELGGTLQYCHSEWIIFRNAIENFALTVKEMAQMLQSFGTELA 180 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LSSVSDLLTYIDDKQLTPELGGTLQYCHSEWIIFRNAIENFALTVKEMAQMLQSFGTELA 180
Qy 181 ETELPDDIPSIEEILAIRAERYHLLKNDITAVTKEGKILLTNLEVPDTEGAVSSRLECHR 240 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ETELPDDIPSIEEILAIRAERYHLLKNDITAVTKEGKILLTNLEVPDTEGAVSSRLECHR 240
Qy 241 QISGDWQTINKLLTQVHDMETAFDGFWEKHQLKMEQYLQLWKFEQDFQQLVTEVEFLLNQ 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QISGDWQTINKLLTQVHDMETAFDGFWEKHQLKMEQYLQLWKFEQDFQQLVTEVEFLLNQ 300
Qy 301 QAELADVTGTIAQVKQKIKKLENLDENSQELLSKAQFVILHGHKLAANHHYALDLICQRC 360 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QAELADVTGTIAQVKQKIKKLENLDENSQELLSKAQFVILHGHKLAANHHYALDLICQRC 360
Qy 361 NELRYLSDILVNEIKAKRIQLSRTFKMHKLLQQARQCCDEGECLLANQEIDKFQSKEDAQ 420 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NELRYLSDILVNEIKAKRIQLSRTFKMHKLLQQARQCCDEGECLLANQEIDKFQSKEDAQ 420
Qy 421 KALQDIENFLEMALPFINYEPETLQYEFDVILSPELKVQMKTIQLKLENIRSIFENQQAG 480 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 KALQDIENFLEMALPFINYEPETLQYEFDVILSPELKVQMKTIQLKLENIRSIFENQQAG 480
Qy 481 FRNLADKHVRPIQFVVPTPENLVTSGTPFFSSKQGKKTWRQNQSNLKIEVVPDCQEKRSS 540 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 FRNLADKHVRPIQFVVPTPENLVTSGTPFFSSKQGKKTWRQNQSNLKIEVVPDCQEKRSS 540
Qy 541 GPSSSLDNGNSLDVLKNHVLNELIQTERVYVRELYTVLLGYRAEMDNPEMFDLMPPLLRN 600 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GPSSSLDNGNSLDVLKNHVLNELIQTERVYVRELYTVLLGYRAEMDNPEMFDLMPPLLRN 600
Qy 601 KKDILFGNMAEIYEFHNDIFLSSLENCAHAPERVGPCFLERKDDFQMYAKYCQNKPRSET 660 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 KKDILFGNMAEIYEFHNDIFLSSLENCAHAPERVGPCFLERKDDFQMYAKYCQNKPRSET 660
Qy 661 IWRKYSECAFFQECQRKLKHRLRLDSYLLKPVQRITKYQLLLKELLKYSKDCEGSALLKK 720 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 IWRKYSECAFFQECQRKLKHRLRLDSYLLKPVQRITKYQLLLKELLKYSKDCEGSALLKK 720
Qy 721 ALDAMLDLLKSVNDSMHQIAINGYIGNLNELGKMIMQGGFSVWIGHKKGATKMKDLARFK 780 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 ALDAMLDLLKSVNDSMHQIAINGYIGNLNELGKMIMQGGFSVWIGHKKGATKMKDLARFK 780
Qy 781 PMQRHLFLYEKAIVFCKRRVESGEGSDRYPSYSFKHCWKMDEVGITEYVKGDNRKFEIWY 840 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 PMQRHLFLYEKAIVFCKRRVESGEGSDRYPSYSFKHCWKMDEVGITEYVKGDNRKFEIWY 840
Qy 841 GEKEEVYIVQASNVDVKMTWLKEIRNILLKQQELLTVKKRKQQDQLTERDKFQISLQQND 900 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 GEKEEVYIVQASNVDVKMTWLKEIRNILLKQQELLTVKKRKQQDQLTERDKFQISLQQND 900
Qy 901 EKQQGAFISTEETELEHTSTVVEVCEAIA SVQAEANTVWTEASQSAEISEEPAEWSSNYF 960 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 EKQQGAFISTEETELEHTSTVVEVCEAIA SVQAEANTVWTEASQSAEISEEPAEWSSNYF 960
Qy 961 YPTYDENEEENRPLMRPVSEMALLY 985
|||||||||||||||||||||||||
Db 961 YPTYDENEEENRPLMRPVSEMALLY 985
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art of method of treating retinal degeneration as disclosed in LaVail by substituting the gene product with Dbl3 as disclosed in Zihni/Zihni(2) in the AAV2, by activating cdc42 to initiate phagocytosis, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in art would be motivated to do so as functional CDC42 is important for correcting tissue organization during retinal development, and its absence leads to severe destabilization of the postnatal retina with strong degeneration and loss of retinal function (abstract). Absent evidence of any unexpected results, one of skill in the art would have been expected to have a reasonable expectation of success in overexpressing Dbl3 to activate cdc42 in RPE cells because prior art successfully reported overexpression of Dbl3 in order to activates apical Cdc42 and thereby stimulates two effector mechanisms: induction of apical MLC phosphorylation by MRCK and aPKC-stimulated downregulation of junctional RhoA-dependent actomyosin contractility (see Zihni). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejections, they are addressed as follows:
Applicant disagree with the rejection arguing LaVail pertains to replacement of defective MERTK with hMERTK and none of the cited documents teach or suggest expression of a functional Dbl3 polypeptide in RPE cells to treat retinal dysfunction or degeneration... Therefore, one of ordinary skill would have understood that the teachings of the cited references amount to a mere invitation to experiment without any guidance a prior of arriving at the claimed method. Applicants continue to argue fails to provide any teaching to apply Db13 expressing nucleic acid sequences in a therapeutic context, let alone for the treatment of retinal dysfunction and/or degeneration (as claimed). Applicants’ arguments have been fully considered but are not found persuasive.
In response to applicants’ argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., expression of a functional Dbl3 polypeptide in RPE cells in any therapeutic context) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have further engaged in selective reading of the teachings of LaVail to formulate the grounds for not teaching away. It should be noted that the ultimate goal of over expressing Dbl3 is to increase phagocytosis of photoreceptor outer segment following direct administration of the vector to retina. As previously indicated, LaVail. in describing a method of treating retinal degeneration, by subretinal injections of the AAV2 vector encoding a gene product (hMERTK) under the control of VMD2-promoter (RPE cell specific promoter) in a subject. Mahajan provides evidence of overexpression of MerTK facilitated the phosphorylation of Vav1, a guanine nucleotide-exchange factor (GEF), which activates Cdc42 (abstract). Heynen reported that functional CDC42 is important for correct tissue organization already during retinal development. It is further disclosed that its absence leads to severe destabilization of the postnatal retina with strong degeneration and loss of retinal function (abstract). A number of genes including Dbl3 overexpression was known to function as a GEF that stimulates CDC42. Thus, Zhini cures the deficiency by suggesting that overexpressing Dbl3 activates apical Cdc42. Applicants' selective reading of LaVail. ignores the teachings of the reference of Mahajan, Zhini. There is no requirement for LaVail. to teach that which is clearly taught by Heynen and Zihni. It should be noted that obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). To the extent, prior art teaches overexpression of Dbl3 stimulates CDC42, it is applicable to the rejection. Absent evidence of any unexpected and/or superior results, a person of ordinary skill in the art would be motivated to modify the method of treating retinal degeneration as disclosed in LaVail by substituting the gene product with Dbl3 as disclosed in Zihni/Zihni(2), to stimulate CDC42 and thereby initiate phagocytosis, as instantly claimed, with a reasonable expectation of success. The method would allow overexpression of Dbl3 to activate cdc42 in RPE cells, with a reasonable expectation of success.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
New-Claim Rejections - 35 USC § 112- necessitated by amendments
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 the applicant regards as his invention.
Claims 14-18, 22, 25 and 26 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 14 recites the limitation "the route " in line 8. There is insufficient antecedent basis for this limitation in the claim. Claims 15-18, 22, 25 and 26 directly or indirectly depend from the rejected base claim. Appropriate correction is required.
Conclusion
No claims allowed.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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