DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/25/26 has been entered. As requested, the claim amendment and response filed on 6/22/26 has also been entered. Claims 1-2, 6-7, 9-10, 13-15, 17-18, 28, 37, 43-45, and 49 remain pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 112
The rejection of claims 17-18, 28, 37, 42-45, and 49 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1-2, 6-7, 9-10, and 13-15 under 35 U.S.C. 103 as being unpatentable over O’Callaghan et al. (September, 2016) Invest. Opthamol. Vis. Science, Vol. 57, 793, abstract, pages 1-2, hereafter referred to as O’Callaghan 2016, in view of Mamiya et al. (2004) Exp. Eye Research, Vol. 79, 405-410, and GenBank Accession Number BC074815 (2005) Homo sapiens matrix metallopeptidase 3 (stromelysin 1), is withdrawn in view of new grounds of rejection set forth below.
Claims 1-2, 6-7, 9-10, 13-15, 17-18, 28, 37, 43-45, and 49 are newly rejected under 35 U.S.C 103 as being unpatentable over O’Callaghan et al. (September, 2016) Invest. Opthamol. Vis. Science, Vol. 57, 793, abstract, pages 1-2, hereafter referred to as O’Callaghan 2016, in view of Mohan et al. (2013) The Ocular Surface, Vol. 11(3), 150-164, Mamiya et al. (2004) Exp. Eye Research, Vol. 79, 405-410, Bradely et al. (1998) IOVS, Vol. 39(13), 2649-2658, and GenBank Accession Number BC074815 (2005) Homo sapiens matrix metallopeptidase 3 (stromelysin 1).
O’Callaghan 2016 teaches a pseudotyped AAV 2/9 vector comprising a CMV promoter operatively linked to a murine MMP3 coding sequence (O’Callaghan 2016, abstract page 1). O’Callaghan 2016 teaches intracameral injection of the AAV 2/9-MMP3 vector into the anterior chamber of the eye in a mouse, where MMP3 is expressed in the corneal epithelium and secreted into the aqueous humor of the eye (O’Callaghan 2016, abstract pages 1-2). O’Callaghan 2016 further teaches that expression of MMP3 in the eye significantly increased paracellular permeability to 70kDa dextran (a tracer molecule) 114-fold, reduced TEER values by 23%, and significantly increased outflow facility (O’Callaghan 2016, abstract pages 1-2). O’Callaghan et al. states that these results represent a realistic rationale for gene therapy of glaucoma (O’Callaghan et al., abstract page 2).
While O’Callaghan et al. teaches that AAV2/9 effectively transduces cells in the anterior chamber of the eye following delivery of the AAV2/9 vector to the anterior chamber of the eye via intracameral injection, particularly corneal epithelium, O’Callaghan et al. does not teach whether AAV2/9 can also transduce cells in the anterior chamber, including corneal cells, in human eyes. However, at the time of filing, it was well known that AAV2/9 can transduce cells in the eye including cells in the anterior chamber which include corneal cells. Mohan et al., for examples, teaches that several single stranded AAV vector serotypes including AAV2/9 efficiently transduce both mouse and human corneal cells (Mohan et al., page 156).
O’Callaghan et al. further differs from the instant invention by not teaching to use a human MMP3 coding sequence, or more specifically a human MMP3 sequence which is at least 95% identical to SEQ ID NO:1. Mamiya et al. supplements O’Callaghan et al. by teaching the delivery of a plasmid encoding human MMP3 under transcriptional control of the CMV promoter to the eye in rabbits and the effects of expression of human MMP3 on intraocular pressure following trabeculectomy surgery, a widely used surgical means for treating glaucoma (Mamiya et al., pages, 405-406). Mamiya et al. teaches that expression of human MMP3 significantly decreased intraocular pressure following trabeculectomy and that the expression of human MMP-3 may be used for glaucoma patients (Mamiya et al., abstract, and pages 405-408). Note that Mamiya et al. specifically states that, “[t]rabeculectomy following MMP-3 transfection caused significantly longer survival of filtering bleb and decreased levels of IOP in comparison with controls (trabeculectomy alone or trabeculectomy following vector transfection)” (Mamiya et al., abstract). Thus, Mamiya et al. showed that expression of human MMP3 affected IOP.
While Mamiya et al. tested the effects of expressed human MMP3 in rabbits and in conjunction with trabeculectomy, Bradely et al. demonstrates that purified human MMP3 (stromelysin) can increase outflow facility of the trabecular meshwork in a human donor eye anterior segment perfused organ culture, where the anterior segment comprises undisturbed trabecular meshwork sandwiched between the intact cornea and a 15mm rim of sclera, by increasing extracellular matrix (ECM) turnover in the meshwork (Bradely, pages 2650-2651 and 2653). Bradely et al. further suggests that modulating aqueous outflow by manipulating matrix metalloproteinase activity may ameliorate intraocular pressure elevation in glaucoma (Bradely, pages 2656-2657).
Therefore, in view of the motivation provided by Mamiya et al. to reduce intraocular pressure by expressing human MMP-3 in the eye using an expression vector for the treatment of glaucoma, the further motivation provided by Bradely et al. that human MMP-3 can increase trabecular meshwork extracellular matrix (ECM) turnover and increase outflow from the trabecular meshwork in the anterior chamber of the human eye which may be useful for glaucoma therapy, and the teachings of Mohan et al. that AAV2/9 effectively transduces cells of the anterior chamber of eye in mouse and humans, it would have been prima facie obvious to the skilled artisan at the time of filing to make an AAV2/9 encoding a human MMP3 sequence instead of a mouse MMP3 sequence in the AAV vector taught by O’Callaghan et al. and to use said vector to treat glaucoma by intracameral injection of the AAV2/9 vector encoding human MMP3 under operative control of the CMV promoter into the eye in order as set forth in O’Callaghan et al. to reduce intraocular pressure associated with glaucoma in the eye of a mammal including a human, modify the ECM of the trabecular meshwork to increase permeability, and increase outflow of the trabecular meshwork all with a reasonable expectation of success.
Further in regards to the sequence of human MPP3, it is noted that Mamiya et al. does not teach the exact sequence of the human MPP3 present in their expression vector. However, various nucleotides sequences encoding human MMP3 were known in the prior art, including the sequence set forth in GenBank Accession Number BC074815 which is 100% identical to SEQ ID NO:1. Therefore, as a number of nucleotide sequences encoding human MMP3 were known in the prior art, including a sequence with 100% identity to SEQ ID NO:1, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize the sequence of GenBank Accession Number BC074815 as the human MMP3 encoding nucleotide sequence in the AAV2/9 vector by O’Callaghan et al. in view of Mohan et al., Mamiya et al., and Bradely et al. as the substitution of one known human MMP3 encoding sequence for another represents nothing more than the substitution of an art recognized equivalent with predictable results.
Applicant’s arguments as they apply to the new grounds of rejection have been fully considered but have not been found persuasive as discussed in detail below.
The applicant reiterates their prior arguments that O’Callaghan 2016 only teaches an AAV vector encoding mouse MMP-3. According to applicant, the rejection does not provide any motivation to substitute human MMP-3 taught by Mamiya et al. for the mouse MMP-3 in the AAV vector taught by O-Callaghan et al. According to applicant, similarity of function between human and mouse MMP-3 is not equivalent to a reason to combine the references. The applicant further reiterates their argument that Mamiya et al. does not teach an AAV vector as claimed and only teaches a pTracer-CMV-vector containing human MMP-3, and that Mamiya et al. does not teach injection of any vector into the anterior chamber of the eye, but rather teaches expression of human MMP3 in rabbit conjunctiva in a method of treating glaucoma that includes trabeculectomy which is different methodology than O’Callaghan 2016. The applicant argues that whereas O’Callaghan shows that mouse MMP-3 modulates cells of the natural outflow pathway, the Schlemm’s canal, Mamiya only shows that human MMP-3 can support a filtering bleb and has no effect on IOP or natural outflow. Thus, the applicant argues that mouse MMP-3 and human MMP-3 have not been shown to be equivalents. In addition, the applicant argues that the prior art shows differences in the transduction efficiency of neural tissue using AAV and toxicity in different species, citing Gray et a., Hinderer et al., and Fang et al., and that the cited art does not show that AAV2/9 can successfully transduce human eye tissue.
In response, the instant rejection as set forth above renders the majority of applicant’s arguments moot. Specifically, Bradely et al. clearly and specifically shows that human MMP-3 delivered to the anterior chamber of a human eye in organ culture can increase outflow facility of the trabecular meshwork in the human donor eye anterior segment perfused organ culture, by increasing extracellular matrix (ECM) turnover in the meshwork and specifically suggests that human MMP-3 modification of the ECM of the trabecular meshwork which increase outflow facility of the trabecular meshwork can ameliorate intraocular pressure elevation in glaucoma. Thus, the cited art of record Bradely et al. provides substantial and specific motivation to deliver human MMP-3 to the anterior chamber of the eye, including a human eye, for treating glaucoma by demonstrating the human MMP-3 can increase can modify the ECM of the trabecular network thereby increasing outflow of the trabecular network. Further, Mamiya at al. shows that a nucleic acid encoding human MMP-3 can be delivered to the eye resulting in transduction of eye cells such as corneal cells. Mamiya et al. was not cited for teaching a method of delivery directly to the anterior chamber, or for delivery to a subject in the absence of trabeculectomy, Mamiya et al. was simply cited to show that expression vectors encoding human MMP-3 can be successfully made and that cells transduced with the vector in the eye express functional human MMP-3. It is also noted that applicant’s argument that Mamiya et al. does not show any functional effect of human MMP-3 expression on intraocular pressure is inaccurate. Mamiya et al. specifically states that, “[t]rabeculectomy following MMP-3 transfection caused significantly longer survival of filtering bleb and decreased levels of IOP in comparison with controls (trabeculectomy alone or trabeculectomy following vector transfection)” (Mamiya et al., abstract). Thus, Mamiya et al. showed that expression of human MMP3 itself affected IOP. Furthermore, concerning applicant’s argument that AAV2/9 shows differences in the transduction efficiency of neural tissue using AAV and toxicity in different species, it is noted that applicant’s cited art does not involve the use of AAV2/9 in the eye of any mammalian species. In contrast, O’Callaghan et al., the primary reference, already teaches that AAV2/9 is efficient in both transducing cells in the anterior chamber of the eye of a mouse following intracameral injection, and Mohan et al. teaches that several single stranded AAV vector serotypes including AAV2/9 efficiently transduce both mouse and human corneal cells of the eye. Thus, based on the teachings of O’Callaghan et al., Mohan et al., Mamiya et al., and Bradely et al., the skilled artisan would have 1) had a reasonable expectation that AAV2/9 encoding a gene such as human MMP-3 under transcriptional control of the constitutive CMV promoter could be effectively delivered by intracameral injection to cells of the anterior chamber of the eye of mammals including mice and humans such that functional human MMP-3 would be expressed in the anterior chamber, and 2) that the expression of human MMP-3 in the anterior chamber of eye would be capable of modifying the ECM of the trabecular network resulting in increased outflow and a decrease in intraocular pressure in the eye without trabeculectomy, and 3) that such a method could be used to treat glaucoma in mammals including humans.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
