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 .
Status of Application, Amendments, And/Or Claims
The Applicants amendments/remarks received 9/3/2025 are acknowledged. No claims are amended; claims 3, 10, 12-15, 17-21, 31, 36, 39, 42-43, 47-48, 54-56, 58-59, 62, 64-71, 75-79, 81, 83, 87, 90, 94-99, 101-108 and 120-121 are canceled; no claims are withdrawn; claims 1-2, 4-9, 11, 16, 22-30, 32-35, 37-38, 40-41, 44-46, 49-53, 57, 60-61, 63, 72-74, 80, 82, 84-86, 88-89, 91-93, 100, 109-119 and 122 are pending and have been examined on the merits.
Information Disclosure Statement
The information disclosure statements submitted on 9/3/2025 and 10/10/2025 have been considered by the examiner.
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 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.
Claims 1-2, 4-9, 11, 16, 22-30, 32, 45-46, 49-53, 57, 60-61, 63, 72-74, 80, 82, 84-86, 88-89, 91-93, 100, 109-119 and 122 are rejected under 35 U.S.C. 103 as being unpatentable over Blumenkranz et al., US 2019/0151409 (U.S. Patent Application Publication cite 10, IDS, 12/23/2020; herein “Blumenkranz”) in view of Yamashita et al., US 2011/0190250 (cite A, PTO-892, 2/7/2023; herein “Yamashita”) and Li et al., US 2021/0189429 (cite A, PTO-892, 9/12/2023; herein “Li”).
Blumenkranz teaches methods for the treatment of neovascular (i.e., “wet”) age-related macular degeneration (AMD) in a subject ([0005-6], [0008], [0019], [0122], [0126], [0130-131], claim 2) comprising the intravitreal administration (i.e. to an eye of the subject) of a recombinant adeno-associated viral vector (i.e. rAAV particles) having a nucleic acid sequence that encodes an anti-VEGF agent, wherein the anti-VEGF agent is aflibercept (Abst.) wherein the individual is a human and the rAAV particles comprise an AAV2 capsid protein comprising an amino acid sequence LGETTRP inserted between positions 587 and 588 of the capsid protein, wherein the amino acid residue numbering corresponds to an AAV2 VP1 capsid protein, and a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of instant SEQ ID NOS: 41 and 35 (i.e., aflibercept) and flanked by AAV2 inverted terminal repeats (ITRs) ([0005-7], [0044], [0028]), wherein the administered unit dose of rAAV particles for intravitreal administration to a human patient can be 1 x 1010 vector genomes (vg) to 6 x 1011 vector genomes ([0071], [0108], [0110-113], [0140-141]). Blumenkranz repeatedly discloses (e.g. [0061]) that the intravitreal administration of the rAAV2-aflibercept is to an eye of the subject; hence, a person of ordinary skill in the art at the time of filing would have found it obvious that the intravitreal administration of the rAAV2-aflibercept can be to one eye and/or the contralateral eye of the subject.
Blumenkranz does not teach that the method to treat AMD further comprises administering difluprednate; however, a person of ordinary skill in the art at the time of filing would have found it obvious for the method to treat AMD to further comprise administering difluprednate in view of Yamashita.
Yamashita teaches that AMD is associated with macular edema [0002] and teaches methods of treating AMD [0004] and macular edema [0006] in human subjects comprising topically administering difluprednate to the eye of the affected individual to improve visual acuity and decrease foveal retinal thickness (Abst.), wherein the difluprednate is at a concentration of 0.05% (w/v) and the dose is a drop (~50 µl), i.e., ~2.5 µg [0031].
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method for treating AMD and associated macular edema made obvious by Blumenkranz in view of Yamashita comprising the intravitreal administration of 1 x 1010 to 6 x 1011 vg/eye rAAV particles expressing aflibercept and the topical instillation of ~2.5 µg of 0.05% (w/v) difluprednate.
Because the rAAV particles expressing aflibercept and difluprednate have different administration routes (intravitreal administration of the rAAV particles expressing aflibercept and topical instillation of difluprednate), it would be prima facie obvious to administer either immediately before or after the other because it would be cumbersome, if not impossible, to administer both simultaneously.
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method for treating AMD and associated macular edema made obvious by Blumenkranz in view of Yamashita comprising the topical administration of ~2.5 µg of 0.05% (w/v) difluprednate to an eye of a patient followed by the intravitreal administration of 1 x 1010 to 6 x 1011 vg/eye rAAV particles expressing aflibercept to the eye of the patient.
Blumenkranz and Yamashita do not address reducing inflammation associated with administering recombinant adeno-associated virus (rAAV) particles by topically administering difluprednate about one week prior to the intravitreal administration of the rAAV particles to the eye of the subject; however, a person of ordinary skill in the art at the time of filing would have found it obvious to further administer topical difluprednate to the eye of the subject about a week prior to the intravitreal administration of the rAAV particles to the eye of the subject in view of the disclosure of Li.
Li discloses that intravitreal AAV2 gene therapy can cause adverse events comprising inflammation, hypertension, hemorrhage, pain, vitritis, conjunctivitis, etc. (rAAV particle therapeutic can be rAAV2 particles [0056]; rAAV2 can be administered intravitreally; [0034-5], [0043], [0158], [0162], [0204]; Example 2, [0268]; Example 6, [0277-8]; Example 15, [0324-361]; [0055], [0188-189], [0357-358], [0610]; Table 8) and that topical ocular administration ([0234], [0247], [0257]) of a steroid prior to the injection can reduce said adverse events and result in higher recovery of vision ([0055], [0188-189], [0608-610]). Li teaches that the topical administration of steroid can be 7 days before rAAV2 particle administration (Example 15, [0324-361]) and that the steroid can be a synthetic analog of prednisolone ([0044], [0167], [0566]; claim 22) which can be an ester [0247] wherein the ester can be ethyl, methyl, isobutyl, ethylene glycol or the like [0244]; hence, the topical steroid administered 7 days before the rAAV2 injection to reduce adverse events, such as inflammation, due to the AAV2 intravitreal injection in the method disclosed by Li encompasses difluprednate which is a butyrate ester derivative of prednisolone, i.e. a synthetic analog of prednisolone. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to modify the method made obvious by Blumenkranz in view of Yamashita to include an additional topical administration of the difluprednate 7 days before the rAAV2-aflibercept intravitreal administration to reduce inflammation associated with rAAV2 injection because Li teaches that topical administration of a steroid, such as difluprednate, a synthetic analog of prednisolone, 7 days before the intravitreal rAAV2 injection reduces adverse events such as inflammation; therefore, claims 1, 16, 29-30, 32, 45-46, 49 and 80 are prima facie obvious.
Regarding claims 22-23, 50 and 111, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li on ALL eyes affected with AMD and associated edema with the method made obvious by Blumenkranz in view of Yamashita and Li discussed above; therefore, claims 22-23, 50 and 111 are prima facie obvious.
Regarding claims 11, 60-61, 63, 110 and 119, Blumenkranz teaches that the individual can be pretreated with Eylea (i.e., aflibercept protein administered by intravitreal injection) before receiving the gene therapy method of treatment, i.e., intravitreal injection of rAAV particles expressing aflibercept, discussed above ([0024], [0033], [0132]). Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li wherein the individual is administered an anti-VEGF agent (aflibercept) by intravitreal injection before practicing the method made obvious by Blumenkranz in view of Yamashita and Li discussed above; therefore, claims 11, 60-61, 63, 110 and 119 are prima facie obvious.
Blumenkranz teaches that the individual with an ocular neovascular disease can be pretreated with Eylea (aflibercept protein administered by intravitreal injection) and assessed for aflibercept responsiveness before the administration of the rAAV particles expressing aflibercept [0132]. Blumenkranz discloses that the effectiveness of intravitreal injection of aflibercept can be assessed at 4 weeks after injection (Example 1, [0145-163], Table 1, Eylea (aflibercept protein) was administered at day 56 and the effectiveness of the Eylea treatment was assessed at day 84 (28 days later)). Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li wherein the individual with ocular neovascular disease is administered aflibercept within 12 weeks of practicing the method made obvious by Blumenkranz in view of Yamashita and Li discussed above with a reasonable expectation of success because Blumenkranz teaches that the individual with an ocular neovascular disease can be pretreated with aflibercept and assessed for aflibercept responsiveness before the administration of the rAAV particles expressing aflibercept and discloses that aflibercept responsiveness can be assessed 4 weeks after administration; therefore, claims 4 and 6 are prima facie obvious.
Regarding claim 5, Blumenkranz teaches that patients who experienced adverse effects with aflibercept protein administration are candidates for Blumenkranz’s gene therapy method of treatment [0134]. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to perform the method made obvious by Blumenkranz in view of Yamashita and Li discussed above wherein the individual with ocular neovascular disease exhibited retention of retinal fluid refractory to aflibercept treatment with a reasonable expectation of success because Blumenkranz teaches that patients who experienced adverse effects with aflibercept protein administration are candidates for Blumenkranz’s gene therapy method of treatment; therefore, claim 5 is prima facie obvious.
Regarding claims 26 and 28, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li discussed above wherein the amount of rAAV particles administered to each eye is correlated with the severity of the ocular neovascular disease in each eye (i.e. the unit dose of rAAV particle administered to the contralateral eye of the individual comprises the same or less vector genomes per eye (vg/eye) than the unit dose of rAAV particles administered to the one eye of the individual when the contralateral eye has the same or less severe symptoms as the one eye and the unit dose of rAAV particles administered to the contralateral eye of the individual comprises more vector genomes per eye (vg/eye) than the unit dose of rAAV particles administered to the one eye of the individual when the contralateral eye has more severe symptoms as the one eye) with a reasonable expectation of success because the amount of therapeutic aflibercept protein produced in each eye would be expected to be correlated with the dose of rAAV particles administered; therefore, claims 26 and 28 are prima facie obvious.
Regarding claims 24-25 and 27, a person of ordinary skill in the art at the time of filing would have found it obvious that applying the method of treatment to the contralateral eye is not limited as far as time passed after the treatment of the one eye; hence, treatment of the contralateral eye with the method made obvious by Blumenkranz in view of Yamashita and Li discussed above either the same day as treatment of the one eye or at least two weeks after the treatment of the one eye are both obvious with a reasonable expectation of success; therefore, claims 24-25 and 27 are prima facie obvious.
Regarding claims 51-53, Blumenkranz teaches that the unit doses of rAAV particles are in a pharmaceutical formulation comprising sodium chloride, sodium phosphate and surfactant wherein the surfactant can be poloxamer [0117]; therefore, claims 51-52 are prima facie obvious. The specific formulations in claim 53 appear to be conventional pharmaceutical formulations comprising sodium chloride, sodium phosphate and poloxamer wherein there is nothing novel about the formulations; therefore, claim 53 is prima facie obvious.
Regarding claims 57 and 109, Blumenkranz teaches that the unit dose of rAAV particles can be in a volume of 30 µl [0072]; therefore, claims 57 and 109 are prima facie obvious.
Yamashita teaches that the topical administration of ~2.5 µg of 0.05% (w/v) difluprednate continues daily for 4 to 12 weeks, preferably with a taper, preferably with 4 administrations per day for the first 4 weeks, and tapering to one administration per day ([0023-29]; Example 1, [0031]); hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li wherein the topical administration of ~2.5 µg of 0.05% (w/v) difluprednate continues daily for 4 to 12 weeks, preferably with a taper, preferably with 4 administrations per day for the first 4 weeks, and tapering to one administration per day; therefore, claims 72-73 and 112 are prima facie obvious.
Regarding claims 74 and 122, topical administration of difluprednate comprising about four administrations of per day for a week prior to administration of the unit dose of rAAV particles and for about 3 weeks after administration of the unit dose of rAAV particles, followed by about 3 topical administrations of difluprednate per day for about 1 week, followed by about 2 topical administrations of difluprednate per day for about 1 week, and followed by about 1 topical administration of difluprednate per day for about 1 week, is an obvious variant on the taper method of Yamashita which would have a reasonable expectation of success; therefore, claims 74 and 122 are prima facie obvious.
Claims 2, 7-9, 82, 84-86, 88-89, 91-93, 100, 113-118 do not add any limitations to the method of claim 1, rather, they catalog results of practicing the method. The method made obvious by Blumenkranz in view of Yamashita discussed above is 100% methodologically identical to the claimed method of claim 1; hence, the method made obvious by Blumenkranz in view of Yamashita would produce the results of claims 2, 7-9, 82, 84-86, 88-89, 91-93, 100, 113-118; therefore, claims 2, 7-9, 82, 84-86, 88-89, 91-93, 100, 113-118 are prima facie obvious.
Response to Arguments
Applicant's arguments filed 9/3/2025 have been fully considered but they are not persuasive. Applicant argues (Remarks, pp. 16-20) that the rejections over Blumenkranz in view of Yamashita and Li and over Blumenkranz in view of Yamashita, Li and Keravala do not address the amended claims now drawn to a method of reducing inflammation associated with administering recombinant adeno-associated virus (rAAV) particles for treating wet age-related macular degeneration (AMD) in an individual. The rejections set forth above and below address the claims drawn to a method of reducing inflammation associated with administering recombinant adeno-associated virus (rAAV) particles for treating wet age-related macular degeneration (AMD) in an individual.
Applicant argues that Li does not remedy the alleged deficiencies of Blumenkranz and Yamashita because Li is drawn to treating LHON not AMD. Applicant completely ignores that the teachings drawn from Li to be combined with Blumenkranz and Yamashita are Li’s teaching that 1) intravitreal AAV2 gene therapy can cause adverse events comprising inflammation, hypertension, hemorrhage, pain, vitritis, conjunctivitis, etc. (rAAV particle therapeutic can be rAAV2 particles [0056]; rAAV2 can be administered intravitreally; [0034-5], [0043], [0158], [0162], [0204]; Example 2, [0268]; Example 6, [0277-8]; Example 15, [0324-361]; [0055], [0188-189], [0357-358], [0610]; Table 8), 2) that topical ocular administration ([0234], [0247], [0257]) of a steroid prior to the injection can reduce said adverse events and result in higher recovery of vision ([0055], [0188-189], [0608-610]), 3) that the topical administration of steroid can be 7 days before rAAV2 particle administration (Example 15, [0324-361]), 4) that the steroid can be a synthetic analog of prednisolone ([0044], [0167], [0566]; claim 22) which can be an ester [0247] wherein the ester can be ethyl, methyl, isobutyl, ethylene glycol or the like [0244]. Hence, administration of a topical steroid, which can be difluprednate, which is a butyrate ester derivative of prednisolone, 7 days before the rAAV2 injection to reduce adverse events, such as inflammation, due to the AAV2 intravitreal injection is clearly obvious over the disclosure of Li; therefore, Applicant’s allegations are completely unpersuasive.
Applicant argues that Li does not teach administering difluprednate, arguing that Li only is reciting synthetic analogs of triamcinolone hexacetonide, not any other steroid because of the syntax of paragraphs [0044], [0167] and [0566]. This is incorrect. In [0044], [0566] and claim 22 (pp. 208-209), Li lists Markush groups of steroids - wherein the steroid is selected from the group consisting of - which ends “...triamcinolone diacetate, and triamcinolone hexacetonide or a synthetic analog thereof.”; hence, “and triamcinolone hexacetonide” closes the Markush group and “or a synthetic analog thereof” applies to all of the steroids listed in the Markush group. In [0167], Li presents the steroids in a list of alternatives concluding with “triamcinolone hexacetonide or a synthetic analog thereof, or a combination thereof”. Triamcinolone hexacetonide cannot form a combination with itself; hence, the limitation “a synthetic analog thereof, or a combination thereof” applies to all of the steroids in the list not just triamcinolone hexacetonide. Hence, Applicant’s interpretation of Li is incorrect.
Additionally, Li discloses that the “agent(s) useful in the present disclosure”, i.e., steroids, comprise the agents, or pharmaceutically acceptable salts, esters, or amides thereof, can be delivered to the subject by topical administration [0247]. Li further discloses that “A pharmaceutically acceptable ester or amide refers to those which retain biological effectiveness and properties of the agents used in the present disclosure, and which are not biologically or otherwise undesirable. Typical esters include ethyl, methyl, isobutyl, ethylene glycol, and the like. Typical amides include unsubstituted amides, alkyl amides, dialkyl amides, and the like.” [0244]. Hence, Applicant’s allegation that Li’s recitation of synthetic analogs applies only to triamcinolone hexacetonide is completely contrary to the actual disclosure of Li.
Applicant alleges that the selection of difluprednate from the list of steroids in Li is “pick and choose features disclosed therein in vacuum” which is “only possible by use of impermissible hindsight.” (p. 17). This is incorrect as Yamashita clearly discloses administering difluprednate. Li is used to modify Blumenkranz in view of Yamashita to extend the administration of the difluprednate to 7 days before the administration of the therapeutic rAAV particles; hence, nothing is being pulled from a vacuum and impermissible hindsight has not been employed.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant alleges (pp. 17-20) that the method encompassed by the pending claims results in unexpected and surprising data with the topical administration of difluprednate. This argument was addressed in the previous Office action (duplicated below). Applicant did not address any of the points raised in the previous Response to Arguments, rather, Applicant simply restates the same argument. This is unpersuasive and the rejection is maintained.
Applicant alleges that this unexpected result is that difluprednate mitigates inflammation associated with administering AAV particles; however, Li et al., US 2021/0189429 (cite A, PTO-892, 9/12/2023; herein “Li”) teaches that intravitreal AAV2 gene therapy (rAAV particle therapeutic can be rAAV2 particles [0056] and that the rAAV2 particle therapeutic can be administered intravitreally ([0034-5], [0043], [0158], [0162], [0204], Example 2, [0268]; Example 6, [0277-8]; Example 15, [0324-361])) can cause adverse events comprising inflammation, hypertension, hemorrhage, pain, vitritis, conjunctivitis, etc. ([0055], [0188-189], [0357-358], [0610]; Table 8) and that topical ocular administration ([0234], [0247], [0257]) of a steroid, which can be a synthetic analog of prednisolone (difluprednate is the difluorinated butyrate ester derivative of prednisolone acetate; thus, a synthetic analog of prednisolone) ([0044], [0167], [0566]; claim 22), can result in lower adverse events that the intravitreally-administered rAAV2 particle therapeutic without the steroid and result in higher recovery of vision ([0055], [0188-189], [0608-610]). Li teaches that the steroid (2nd pharmaceutical composition) is administered before the administration of the rAAV particle therapeutic, then administered after the administration of the rAAV particle therapeutic for several weeks wherein the dosage of the steroid is gradually tapered down [0047-49]. Li demonstrates their therapeutic regimen on human patients comprising administration of steroid for 7 days before rAAV2 particle administration, intravitreal injection of the rAAV2 particle therapeutic, then administration of the steroid for 7 weeks following the injection of the rAAV2 particles with a gradually tapering dosage resulted in lower adverse events that with the intravitreal administration of the rAAV2 therapeutic alone (Example 15, [0324-361]).
Thus, it is not unexpected that intravitreal administration of an rAAV2 therapeutic can cause adverse events including inflammation, nor is it unexpected that topical administration of a steroid, which can be a synthetic analog of prednisolone, e.g. difluprednate, which can be for 7 days before the administration of the rAAV therapeutic, ameliorates the adverse events.
Thus, Applicant’s alleged “surprising and unexpected finding” that administering difluprednate could mitigate ocular inflammation caused by a single IVT injection of AAV2.7m8-aflibercept at doses of about 1 x 1010 vg to about 6 x 1011 vg” is clearly not unexpected in view of the prior art.
To successfully argue for secondary consideration based on unexpected results, several considerations are employed as discussed in MPEP 716:
A) Evidence of unexpected results are weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. Applicant argues that difluprednate eye drops were effective for resolving ocular inflammation in the subjects caused by the intravitreal administration of AAV2.7m8-aflibercept (pp. 19-20); however, this is not an unexpected result as Yamashita clearly teaches that difluprednate eye drops are effective for resolving ocular inflammation in the subjects [0010] as well as for treating macular edema associated with AMD ([0002], [0004], [0035]). Additionally, Li discloses that intravitreal administration of rAAV2 therapeutics can cause adverse events including inflammation and sets forth methods for ameliorating the adverse events with steroid administration which encompasses topical administration of synthetic analogs of prednisolone, e.g. difluprednate, for 7 days before rAAV2 particle administration, intravitreal injection of the rAAV2 particle therapeutic, then administration of the steroid for 7 weeks following the injection of the rAAV2 particles with a gradually tapering dosage. Hence, the instantly claimed method appears to be obvious over the prior art and the effectiveness of difluprednate to resolve adverse events from the intravitreal administration of rAAV2 therapeutics, rather than being unexpected, is what is taught by the prior art.
B) Alleged unexpected results must be commensurate in scope with the claimed invention. Independent claim 1 recites a topical difluprednate treatment about a week before administration of the unit dose of rAAV particles wherein the dosage of difluprednate can be any de minimus amount of difluprednate and wherein NO treatment with difluprednate after the administration of the unit dose of rAAV particles is required.
Thus, the claims encompass treatments comprising administration of 0.000001 ng of difluprednate 7 days before administration of the unit dose of rAAV particles with no subsequent administration of difluprednate.
The treatment of cohorts 3, 4a and 4b in the original disclosure do not comprise administration of difluprednate before the administration of the unit dose of rAAV particles. Hence, the method relied on for the unexpected results allegation, the treatment of cohorts 3, 4a and 4b in the original disclosure DOES NOT meet the limitations of the claims.
The treatment of cohorts 3, 4a and 4b in the original disclosure require the topical administration of 2.5 mg difluprednate 4 times per day for the first three weeks post AAV administration, 3 times per day for the fourth week, 2 times per day for the fifth week, and once per day for the sixth week.
Thus, the unexpected results are clearly not commensurate in scope with the claimed invention and are unpersuasive as a secondary consideration. None of the dependent claims limit the method to a scope which is commensurate in scope with the alleged unexpected results. See MPEP 716.02(d).
C) To support an allegation of unexpected results, the claimed composition must be compared to the compositions of the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). There is no comparison to the closest prior art, i.e., to the methods of Blumenkranz, Yamashita and/or Li; hence, Applicant's allegation of unexpected results is unsupported. See MPEP 716.02(e).
D) Evidence must show results that are unexpected. As described in detail above, amelioration of the adverse events caused by the intravitreal administration of rAAV2 therapeutics with difluprednate eye drops is in no way unexpected. As described above, Li teaches that steroid administration before and after the administration of the rAAV2 particle therapeutic leads to a higher average recovery of vision than administration of the rAAV2 particle therapeutic alone and that steroid administration before and after the administration of the rAAV2 particle therapeutic leads to a decrease in adverse events, including inflammation, than administration of the rAAV2 particle therapeutic alone and, as described above, Yamashita clearly teaches that difluprednate eye drops are effective for resolving ocular inflammation in the subjects [0010] as well as for treating macular edema associated with AMD ([0002], [0004], [0035]). Hence, Applicant’s alleged unexpected results are not unexpected in view of the prior art.
Applicant’s arguments are unpersuasive and the rejection is maintained.
Claims 1-2, 4-9, 11, 16, 22-30, 32-35, 37-38, 40-41, 44-46, 49-53, 57, 60-61, 63, 72-74, 80, 82, 84-86, 88-89, 91-93, 100, 109-119 and 122 are rejected under 35 U.S.C. 103 as being unpatentable over Blumenkranz in view of Yamashita, Li and Keravala, US 2020/0010851 (cite B, PTO-892, 2/7/2023; herein “Keravala”).
The discussion of Blumenkranz, Yamashita and Li regarding claims 1-2, 4-9, 11, 16, 22-30, 32, 45-46, 49-53, 57, 60-61, 63, 72-74, 80, 82, 84-86, 88-89, 91-93, 100, 109-119 and 122 set forth in the rejection above is incorporated herein.
Blumenkranz teaches that the nucleic acid of the rAAV particles can comprise a first ITR sequence; a promoter sequence; an intron sequence; a first UTR sequence; a sequence encoding aflibercept; a second UTR sequence; a poly A sequence; and a second ITR sequence [0070] but does not specifically teach that the nucleic acid comprises, in a 5’ to 3’ order, (a) a first enhancer region, (b) a promoter region, (c) a 5' UTR region, (d) a nucleic acid encoding a polypeptide comprising an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 35 (aflibercept), (e) a second enhancer region, (f) a polyadenylation site and flanked by AAV2 inverted terminal repeats (ITRs). However, a person of ordinary skill in the art at the time of filing would have found it obvious for the nucleic acid of the rAAV particles to comprise, 5’ to 3’, a first enhancer region, a promoter region, a 5' UTR region, aflibercept, a second enhancer region and a polyadenylation site, flanked by AAV2 ITRs in view of the disclosure of Keravala.
Keravala teaches nucleic acid cassettes which increase the expression of heterologous genes which can be the nucleic acid of rAAV particles (Abst.; [0039], [0131], [0175-8]; Figs. 1, 11). Keravala teaches that the heterologous gene can be aflibercept, that the nucleic acid cassette can be cassette 11 and that the rAAV vector and capsid can be AAV2.7m8 ([0175-8]; Fig. 11) giving the rAAV2 aflibercept construct shown in Fig. 11 which comprises, 5’ to 3’, an AAV2 ITR, a first enhancer region comprising a CMV sequence comprising a sequence having at least 85% identity to SEQ ID NO: 22, a promoter region comprising a CMV sequence comprising at least 85% identity to SEQ ID NO: 23, a 5’ UTR region comprising a TPL sequence comprising at least 85% identity to SEQ ID NO: 24 and an eMLP sequence comprising at least 85% identity to SEQ ID NO: 25, the nucleic acid encoding aflibercept (i.e. a nucleic acid encoding a polypeptide comprising a nucleic acid sequence having at least 85% identity to SEQ ID NO: 40 wherein the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 35 or at least 95% identity to SEQ ID NO: 41), a second enhancer region comprising a full EES sequence with at least 85% identity to SEQ ID NO: 26, a polyadenylation site comprising a HGH polyadenylation site having at least 85% identity to SEQ ID NO: 27 and an AAV2 ITR. Keravala demonstrates that the construct of Fig. 11 gives enhanced production of aflibercept (Figs. 2-4, cassette 11).
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Blumenkranz in view of Yamashita and Li substituting Keravala’s enhanced aflibercept expression cassette 11 for the nucleic acid flanked by ITRs of Blumenkranz with a reasonable expectation of success because Keravala teaches that expression cassette 11 gives enhanced expression of aflibercept; therefore, claims 33-35, 37-38, 40-41 and 44 are prima facie obvious.
Response to Arguments
Regarding the rejection of claims 1-2, 4-9, 11, 16, 22-30, 32-35, 37-38, 40-41, 44-46, 49-53, 57, 60-61, 63-64, 72-74, 80, 82, 84-86, 88-89, 91-93, 100 and 109-122 under 35 U.S.C. 103 as being unpatentable over Blumenkranz in view of Li and Keravala, Applicant argues (pp. 19-20) that Keravala fails to teach or suggest the claimed method of reducing inflammation associated with administering rAAV particles for treating AMD in an individual. Keravala is relied on for disclosing non-naturally occurring polynucleotide cassettes for enhanced expression of a transgene in a mammalian cell, wherein expression of a secretory polypeptide from the polynucleotide cassette in mammalian cells is at least 5 times higher than the expression of the secretory peptide from a reference cassette in the mammalian cells. Blumenkranz in view of Yamashita and Li, as set forth above, make obvious the method of reducing inflammation associated with administering rAAV particles for treating AMD in an individual. Hence, the rejection is maintained.
Conclusion
No claims are 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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/TRENT R CLARKE/ Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651