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 .
Applicants’ arguments and amendments to the claims filed on March 23, 2206 have been received and entered. Claims 14-17, 26 and 27 have been amended. The objection to specification is withdrawn In view of applicant’s amendment to correct the typographical error. Claims 1-12, 14-18, 22, 25-26 and 27 are pending in the instant application.
Election/Restrictions
Applicant’s 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Claims 1-12 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim.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, 25-26 and 27 are under consideration.
Maintained-Claim Rejections - 35 USC § 112-scope of enablement
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, 25-26 and 27 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 in a subject, said method comprising subretinal injection to the subject, an effective amount of AAV-2 or AAV-8 vector comprising a promoter operably linked to a nucleotide sequence as set forth in SEQ ID NO: 3 or 4 encoding a Dbl3 polypeptide, wherein said administration results in increased phagocytosis of photoreceptor outer segment in said subject, thereby treating retinal degeneration in the subject, does not reasonably provide enablement for using naked DNA, or any other vector encoding any other Dbl3 polypeptide or variant thereof including any other Dbl3 polypeptide that is a phosphomimetic delivered via any other route to treat any other condition including retinitis pigmentosa or macular degeneration. 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. a nucleic acid sequence encoding any Dbl3 polypeptide, or an expression construct comprising a promoter operably linked to a nucleic acid sequence encoding a Dbl3 polypeptide or a vector comprising an expression construct comprising a promoter operably linked to a nucleic acid sequence encoding a Dbl3 or a vector comprising a nucleic acid sequence or an expression construct encoding any gene product that rescues phagocytosis of photoreceptor outer segments. The claims encompass a nucleic acid encoding any Dbl3 polypeptide. The, claims as written encompasses variant of Dbl3 and other truncation including 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 characterized by defective phagocytosis of photoreceptor outer segments or aid 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 via any route a naked DNA encoding any Dbl3 polypeptide or administering via any route any expression construct or a vector comprising a promoter operably linked to a nucleic acid sequence encoding a Dbl3 polypeptide. The claims further include administering via any route any vector comprising a nucleic acid sequence or an expression construct encoding any known or yet to be identified gene product that rescues phagocytosis of photoreceptor outer segments. . 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 the 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 . avector 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 comparing 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:
The state of the art teaches twelve natural serotypes of AAV (1-12) that have been characterized to date, having differential tropism and transduction potential in vasculature, retina, brain, muscle, liver, and lung. The process of gene therapy involves several critical steps: selecting the appropriate AAV serotype, choosing the most effective administration route, precisely delivering the vectors to the desired cells, and ensuring the sustained expression of the therapeutic genes, which ultimately leads to the correction or mitigation of the underlying genetic disorder (see Liu Cytokine & Growth Factor Reviews, 2024, 80, 109-120 and references therein page 110, col. 2, para. 1). For instance, serotype like AAV1 show strong affinity for skeletal and cardiac muscle, making them ideal for treating muscular dystrophies and cardiomyopathies. AAV9, AAVrh10, and AAV2 are particularly effective in targeting the CNS, which is crucial for treating neurodegenerative diseases such as SMA and Parkinson’s disease. Meanwhile, AAV2 is widely used in ocular gene therapy for conditions like Leber's Congenital Amaurosis, given its strong affinity for retinal pigment epithelial cells (see page 110, col. 2, para. 2). The art continues to teach on ocular conditions, intravitreal, subretinal, and suprachoroidal injections are employed; intravitreal injections target the retina, while subretinal injections precisely deliver the vector to photoreceptors. Thus, art teaches choice of administration route is guided by the specific disease, target tissue, and therapeutic objectives (see page 111, col. 1, para. 1).. Liu states “several AAV serotypes demonstrate the tropism for retinal cells, however, AAV2 is the most widely utilized serotype in ocular gene therapy, particularly effective in targeting RPE cells and photoreceptors (see page 114, col. 2, last para).
The specification is silent on teaching or providing any guidance on delivering via any route any virus or non-viral vector that is delivered to treat any retinal dysfunction and/or degeneration of any etiology and pathology other than subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter as embraced by the breadth of the claims. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. Moore et al (Expert. Opinion Biol. Therp, 2017, 1235-1244) raise critical issues that need to be addressed include optimizing surgical delivery of vector, the potential risks of chronic expression of antiangiogenic or anti-complement proteins, as well as the unknown long-term tolerability and efficacy of gene therapy in the eye. Moore emphasizes key factors that influence the level of expression include the route of administration (intravitreal vs. subretinal) and the type of virus vector and serotype (which determine the percentage of cells that are transduced), as well as the promoter used to drive expression of the transgene (see page 1242, col. 1, para. 3). MacDonald et al (TVST, 2020, 9(3), 1-9) teaches anatomical differences between the retinas of mouse and primate models, and report that the intravitreal approach may be less effective in humans, especially in treating outer retinal cells. Hence, in primates, the thicker ILM at the vitreo–retinal interphase limits the transduction of cells to a small parafoveal ring even after the injection of novel, mutant capsids with improved cellular transduction in rodents. MacDonald emphasizes “Intravitreal injection of vector is thus currently limited to clinical trials that target diseases that affect the inner retina, such as Leber hereditary optic neuropathy, and diseases such as X-linked retinoschisis where the retinal architecture is affected by the causative mutation. …. Moreover, gene transfer from the vitreous of large eyes is highly inefficient due to dilution of the vector when administered into the vitreous cavity (see page 4, col. 1, para. 2-3). The guidance provided in the specification is limited to a subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter (see Figure 19). The specification does not provide guidance on the use of naked nucleic acid encoding a Db13 or Db13 Y470D, lacking a promoter or other regulatory sequences in the claimed method. Further, the literature at the time of filing does not provide guidance on how to get RNA polymerase to efficiently prime to a DNA strand that lacks a promoter. An artisan would have to perform undue experimentation to first characterize different serotype of AAV or other vector that are capable of transducing RPE cells delivered via different route in vivo treatment of retinal dysfunction and/or degeneration, without reasonable expectation of success.
The specification fails to teach to which extent, any vectors or AAV or other expression vector would transduce cell types present in the eye or any other tissue, nor do they show any expression and/or secretion of a Dbl3 polypeptide that can be expressed by delivering nucleic acid encoding Dbl3 any vector via any route in vivo that exert any therapeutic effect other than subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter (see Figure 19). Thus, given the breadth of the claims, it is apparent that one of skilled in the art would require the identification and characterization of all the different expression vector or serotype of AAV serotype delivered via different route by testing their ability to infect the different cells of eye affected by the plurality of disorder in a predictable animal model to make use of the invention. Given, the variable and unpredictable expression pattern following use of different serotype of AAV or expression vector delivered via different route and the lack of guidance provided by the specification with respect to using any other vector or serotype of AAV encoding nucleotide sequence encoding Dbl3 operably linked to any promoter intended to treat retinal dysfunction and/or degeneration of different etiology and pathology would require undue experimentation for one of skill in the art to make and use the invention, without a reasonable expectation of success.
The claims encompass use of a nucleic acid encoding any Dbl3 polypeptide. The, claims as written encompasses variant of Dbl3 and other truncation including 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. Claim further limits the Dbl3 polypeptide is a phosphomimetic; optionally wherein a) the phosphomimetic mimics phosphorylation of the conserved TERVYVREL activation motif. The claims encompass amino acids substitution within the motif that would rescue the phagocytotic function in the photoreceptor outer segments. The guidance provided in the specification is limited to using a RPE-specific promoter as set forth in SEQ. ID NO:7 that is cloned into AAV vectors along with either Db13 (SEQ ID NO: 3) or DbI3 Y570D (SEQ ID NO: 4). It is emphasized that the transduction of target cells represents the first critical step in any gene-based therapy, which not only depends upon the type of target cells but also on the choice and/or characteristics of delivery vectors. In the instant case, specification teaches subretinal infection of AAV8 comprising a nucleic acid encoding a Dbl3 polypeptide under the control of RPE-specific promoter, wherein the nucleic acid consists of SEQ ID NO: 3 or 4. 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). 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). Therefore, the results exemplified in the instant specification is limited to direct r 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 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, the 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). 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. An artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because transport barriers for vector selection, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for treatment, and identifying the best route were known to be critical and unpredictable parameter in achieving more favorable AAV gene therapy as supported by the observations in the art record.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the full scope of the claimed inventions.
Response to arguments
Applicant disagrees with the rejection arguing claims require the targeting of a functional Dbl3 polypeptide to RPE cells. Accordingly, 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. For example, tests to determine Dbl3 function and identify the claimed polypeptide are described throughout the application as originally filed (see, e.g., page 23 (lines 14 to 20)). Therefore, contrary to the Examiner's opinion, administration of bare polypeptides and untargeted nucleic acids are not encompassed by the claimed methods. As further taught in the present specification, transduction may be performed by any of the viral vectors described (see, e.g., page 29 (line 18) to page 32 (line 19) of the application as filed. Moreover, Examples 8 and 9 demonstrate that an AAV vector, an example of a viral vector, works effectively in vivo. Thus, the skilled person would have been able to administer the claimed expression constructs and vectors using the different viral vectors described without undue experimentation. Furthermore, as described on page 33 (lines 22-24) of the application as filed, multiple suitable routes of administration can be used with the claimed methods, depending on the specific medical use. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, as stated in previous office action, the breadth of the claims encompasses treating retinal dysfunction and/or degeneration of any etiology and pathology said method comprising administering via any route to a subject (having healthy or diseased retina) an expression vector comprising an RPE specific promoter operably liniked to a nucleic acid encoding any functional Dbl3 polypeptide. The claims limit retinal dysfunction and/or degeneration is an inherited retinal disorder or dystrophy, such as retinitis pigmentosa or macular degeneration. The retinal dysfunctional an/or degermation recited in base claim encompasses wet or neovascular AMD or geographic atrophy, or inherited dystrophies such as Stargardt and Sorsby diseases. It is relevant to note that base claim 1 does not even require expression of Dbl3 polypeptide in any cells or increased phagocytosis of photoreceptor outer segment.
The art of record teaches intravitreal, subretinal, and suprachoroidal injections are employed in the treatment of retinal dysfunctional in a subject in need thereof. It is known that intravitreal injections target the retina, while subretinal injections precisely deliver the vector to photoreceptors. Thus, art teaches choice of administration route is guided by the specific disease, target tissue, and therapeutic objectives (see page 111, col. 1, para. 1). Moore et al (Expert. Opinion Biol. Therp, 2017, 1235-1244) emphasizes key factors that influence the level of expression include the route of administration (intravitreal vs. subretinal) and the type of virus vector and serotype (which determine the percentage of cells that are transduced), as well as the promoter used to drive expression of the transgene (see page 1242, col. 1, para. 3). MacDonald et al (TVST, 2020, 9(3), 1-9) teaches anatomical differences between the retinas of mouse and primate models, and report that the intravitreal approach may be less effective in humans, especially in treating outer retinal cells. Hence, in primates, the thicker ILM at the vitreo–retinal interphase limits the transduction of cells to a small parafoveal ring even after the injection of novel, mutant capsids with improved cellular transduction in rodents. MacDonald emphasizes “Intravitreal injection of vector is thus currently limited to clinical trials that target diseases that affect the inner retina, such as Leber hereditary optic neuropathy, and diseases such as X-linked retinoschisis where the retinal architecture is affected by the causative mutation. …. Moreover, gene transfer from the vitreous of large eyes is highly inefficient due to dilution of the vector when administered into the vitreous cavity (see page 4, col. 1, para. 2-3). The guidance provided in the specification is limited to subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter. There is no evidence on record that using construct delivered via any other route of administration to treat retinal dysfunction and/or degeneration other than a direct retinal, intravitreal injection. One of skill in the art would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
In response to applicant’s argument that transduction may be performed by any of the viral vectors or non-viral vector, it is noted that none of the claim require transduction of any target cell in retina using any viral or non-viral vector is not required by the claims under consideration. In fact, independent claim 14 only requires administering to a (any) subject (having healthy retina or diseased retina). The method as such does not require transduction and/or expression of Dbl3 in any target cell of retina. It is emphasized that the transduction of target cells represents the first critical step in any gene-based therapy, which not only depends upon the type of target cells but also on the choice and/or characteristics of delivery vectors. In the instant case, specification teaches subretinal infection of AAV8 comprising a nucleic acid encoding a Dbl3 polypeptide under the control of RPE-specific promoter, wherein the nucleic acid consists of SEQ ID NO: 3 or 4. 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. 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). Therefore, the results exemplified in the instant specification is limited to aa 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 disease encompassed by the independent claims.
In response to applicant’s argument that may one of skill in art could have used any of the viral vectors described for the claimed method, it is emphasized that the specification fails to teach to which extent, any vectors or AAV or other expression vector would transduce cell types present in the eye or any other tissue, nor do they show any expression and/or secretion of a Dbl3 polypeptide that can be expressed by delivering nucleic acid encoding Dbl3 any vector via any route in vivo that exert therapeutic effect other than subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter (see Figure 19).
The specification is silent on teaching or providing any guidance on delivering via any route any virus or non-viral vector that is delivered to treat any retinal dysfunction and/or degeneration of any etiology and pathology other than subretinal injection of AAV-8 vector encoding either Db13 or Db13 Y470D under the control of Best1 promoter as embraced by the breadth of the claims. The previous office action explicitly stated that the process of gene therapy involves several critical steps: selecting the appropriate AAV serotype, choosing the most effective administration route, precisely delivering the vectors to the desired cells, and ensuring the sustained expression of the therapeutic genes, which ultimately leads to the correction or mitigation of the underlying genetic disorder (see Liu Cytokine & Growth Factor Reviews, 2024, 80, 109-120 and references therein page 110, col. 2, para. 1). For instance, serotype like AAV1 show strong affinity for skeletal and cardiac muscle, making them ideal for treating muscular dystrophies and cardiomyopathies. AAV9, AAVrh10, and AAV2 are particularly effective in targeting the CNS, which is crucial for treating neurodegenerative diseases such as SMA and Parkinson’s disease. Meanwhile, AAV2 is widely used in ocular gene therapy for conditions like Leber's Congenital Amaurosis, given its strong affinity for retinal pigment epithelial cells (see page 110, col. 2, para. 2). Liu states “several AAV serotypes demonstrate the tropism for retinal cells, however, AAV2 is the most widely utilized serotype in ocular gene therapy, particularly effective in targeting RPE cells and photoreceptors (see page 114, col. 2, last para). An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
Withdrawn=Claim Rejections - 35 USC § 112-written description
Claims 14-18, 22, 25-26 and 27 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Applicant’s amendment to the claims obviates the basis of the rejection, therefore, previous rejection of claims are hereby withdrawn. .
Withdrawn-Claim Rejections - 35 USC § 112
Claim 17wasrejected 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. In view of applicant’s amendments to claim 17 deleting phrase such as, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn- Claim Rejections - 35 USC § 102
Claims 14-17, 22 and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by LaVail et al (2016,. Adv Exp Med Biol 854:487–493, doi:10.1007/978-3-319-17121-0_65, IDS). Applicant’s argument that claims have been amended to overcome the rejection of record is found persuasive, therefore, previous rejection of claims is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained-Claim Rejections - 35 USC § 103
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, 25-26 and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over LaVail et al (Adv Exp Med Biol 2016,.854:487–493, doi:10.1007/978-3-319-17121-0_65, IDS), 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).
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 construct encoding a gene product is Dbl3 polypeptide.
Heynen reported 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 provide 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 (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) (limitation of claim 27).
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, 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 the 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
Applicant disagree with the rejection arguing none of reference teach or suggest expression of a functional Dbl3 polypeptide in RPE cells to alleviate vision loss. Indeed, neither Zihni reference, alone or in combination with the secondary references, teach or suggest the finding that Db13 drives Cdc42 signaling for the development of a therapy for retinal/ dysfunction and/or degeneration (as taught in the present application). 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’ arguments have been fully considered, but are not found persuasive.
In response to applicant's 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 to alleviate vision loss) 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 argument that cited references amount to a mere invitation to experiment, it appears that applicant in part agree that cited art of record provide motivation to modify the method of LaVail by substituting the gene product with Dbl3 as disclosed in Zihni/Zihni(2). As previously indicated, Heynen reported 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). 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). 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). Applicants' selective reading of LaVail. ignores the teachings of the reference of Peled et al. There is no requirement for Peled et al. to teach that which is clearly taught by Heynen and Zihni . 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 initiate phagocytosis, as instantly claimed, with a reasonable expectation of success, because the method would allow for overexpression of Dbl3 to activate cdc42 in RPE cells as prior art reported overexpression of Dbl3 activates apical Cdc42 and thereby stimulates two effector mechanism as discussed above, 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.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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