Docket No. 17618CON5B (AP)
`
`Exhibit E of Schiffman Declaration 1
`
`Ph^sr? 2 001
`
`Phas?? 3 (P-udy)
`
`3
`
`study)
`
`t)M% CsA in 0 6/5% CO 0,05% CsA in 1.2$% CO 0.05% CsA in 135% CO
`
`Comp&md with OJ.% C«A tn 1,25% CO
`
`srr
`
`.Jic
`{"•Jliiwisi
`
`i'':
`
`0.25
`
`0.2S
`
`1
`•4 Told imD'ovement*) {4 "oirs
`
`*Compir€d to
`
`the 0.05%
`
`CO Phas© 2 formulation {tliscfosftd in 0}ng)
`
`Exhibit F of Schiffman Declaration 1
`
`2 5 1
`
`Sftetivf' S'toa; o> O.OS^t CsA «
`3 vs O OSX CsA in
`
`5.25^ CO ffo-ss
`CO tVc^
`2
`
`SB O-CS^ CsA.: -3^%
`CO
`«B0.0S^ CiA: ;.^C0
`m om% CSA
`i mco
`
`S
`
`:"vl
`
`%
`
`V J»
`
`v;;
`
`B
`1
`J O.S-
`l
`
`iiJ \
`
`2222:
`
`I
`
`3 ' 1 -ii
`1|
`
`ft
`\ ' • si
`
`^
`
`^t
`
`a.
`>
`S
`
`£
`3
`? 5;
`(» STT
`
`11
`
`£ £
`
`
`
`if fffl
`t
`
`It h hhfjfilitf ( f
`5
`t
`
`? y*:V::V:: S
`5: •.<!;} ! V
`Ostrsss* i" Cw^
`
`0198
`
` EXHIBIT 1004 (PART 2 of 3)
`
`

`
`Docket No. 17618CON5B (AP)
`
`This dramatic increase in relative efficacy between the claimed methods and the
`formulation disclosed in Examples IE and ID of Ding was especially unexpected
`in
`As described by Dr. Attar in paragraph 7 of the Attar
`of pharmacokinetic data.
`Declaration, pharmacokinetic studies were performed on animal eyes, which compared
`the pharmacokinetic properties of several cyclosporin A-containing formulations,
`including formulations containing 0.05% by weight cyclosporin A and 0.625% by weight
`castor oil, formulations containing 0.05%) by weight cyclosporin A and 1.25% by weight
`castor oil, and formulations containing 0.1% by weight cyclosporin A and 1.25% by
`weight castor oil.
`This data was compiled and organized in Exhibit B to the Attar
`Declaration, reproduced below:
`
`view
`
`Exhibit B to Attar Declaration
`
`^ 0.05% CsA: 0.625% CO
`m 0.05% CsA: 1.25% CO
`
`xx,.*:/
`
`0.1% CsA: 1.25% CO
`
`'w>>>
`
`\
`
`V/
`
`Sd
`
`Cornea
`
`Conjuctiva
`
`1.5-i
`
`o o
`se to
`
`CM
`
`1.0
`
`tn o
`s?
`o
`B
`o 3 0.5-
`<
`Q>
`
`"S
`a>
`
`o.o
`
`As described in paragraph 7 of the Attar Declaration, this chart shows that the
`amount of cyclosporin A that reaches the cornea and conjunctiva, ocular tissues that are
`highly relevant for the treatment of dry eye or keratoconjunctivis sicca, is higher for the
`
`12
`
`0199
`
`

`
`Docket No. 17618CON5B (AP)
`
`formulation containing 0.05% by weight cyclosporin A and 0.625% by weight castor oil
`(Ding IE) than the formulation containing 0.05% by weight cyclosporin A and 1.25% by
`weight castor oil (the formulation in the claimed methods) relative to the formulation
`containing 0.1 % by weight cyclosporin A and 1.25% by weight castor oil (Ding ID).
`According to Dr. Attar, this data teaches that the claimed methods using the formulation
`containing 0.05%) by weight cyclosporin A and 1.25% by weight castor oil would be less
`therapeutically effective than the formulation containing 0.05% by weight cyclosporin A
`and 0.625% by weight castor oil or the formulation containing 0.10% by weight
`cyclosporin A and 1.25% by weight castor oil. Attar Declaration at
`]{ 8. Similarly,
`according to Dr. Schiffman, this data shows that, since lower levels of cyclosporin A
`were reaching the ocular tissues relevant for the treatment of dry eye, one of skill in the
`art would have expected patients receiving the formulation in the claimed methods to
`exhibit a lesser decrease from baseline in corneal staining score and a lesser increase
`from baseline in Schirmer Score relative to the corneal staining scores and Schirmer
`Scores of the patients receiving the 0.05%) by weight cyclosporin A / 0.625%) by weight
`castor oil formulation (Ding IE) in the Phase 2 trials, as illustrated in Schiffinan
`Declaration 1, Exhibit B. See Schiffman Declaration 1 at 13.
`As described by Dr. Schiffman in paragraphs 14-15 of Schiffinan Declaration 1,
`surprisingly, the claimed method was equally or more therapeutically effective for the
`treatment of dry eye or keratoconjunctivitis sicca than the formulation containing 0.10%
`by weight cyclosporin A and 1.25% by weight castor oil (Ding ID) according to corneal
`staining
`score, Schirmer Score,
`an
`improvement
`in
`the
`common dry
`eye/keratoconjunctivitis sicca symptom of blurred vision and a greater decrease in the
`number of artificial tears used by patients.
`Taking the results of the studies and data presented in the Attar and Schiffinan 1
`Declarations together, it is clear that the specific combination of 0.05% by weight
`cyclosporin A with 1.25% by weight castor oil is surprisingly critical for therapeutic
`
`effectiveness in the treatment of dry eye or keratoconjunctivitis sicca.
`Accordingly, the Applicants submit that the Declarations of Drs. Rhett M.
`Schiffman (Schiffman Declaration 1) and Attar, together with the data presented in those
`
`13
`
`0200
`
`

`
`Docket No. 17618CON5B (AP)
`
`declarations, provide clear and convincing objective evidence that establishes that the
`claimed methods, including administration of a formulation with 0.05% by weight
`cyclosporin A and 1.25% by weight castor oil, demonstrate surprising and unexpected
`results, including improved Schirmer Tear Test scores and corneal staining scores (key
`objective measures of efficacy for dry eye or keratoconjunctivitis sicca) and improved
`visual blurring and reduced artificial tear use as compared to the prior art, for example,
`emulsion formulations disclosed in Ding, including formulations with 0.05%) by weight
`cyclosporin A and 0.625% by weight castor oil (Ding IE) and formulations with 0.10%
`by weight cyclosporin A and 1.25%
`
`
`castor by weight (Ding ID).
`oil
`
`The Claimed Methods are Commercially Successful
`As discussed during the Examiner interview, in addition to having surprising and
`unexpected results, the claimed methods have demonstrated commercial success.
`In
`support of this position, the Applicants submit herewith as Exhibit 3, a Declaration of
`Aziz Mottiwala under 37 C.F.R. § 1.132 (hereinafter, "Mottiwala Declaration"), Vice
`President of Marketing at Allergan
`for Allergan's
`Dry
`Eye
`Product
`Franchise.
`As explained by Mr. Mottiwala, RESTASIS®, which
`is
`a commercial embodiment
`of the claimed methods, has been sold since 2003. See Mottiwala Declaration at ]{ 2.
`Since the launch of RESTASIS® in 2003, worldwide sales of the drug have increased
`steadily. See Mottiwala Declaration at ]{ 3 and Exhibit B to Mottiwala Declaration.
`Currently, annual world-wide net sales for RESTASIS® are over $200 million per
`quarter, and nearing $800 million annually. See Mottiwala Declaration at ]{ 4. This is
`strong evidence of commercial success. See Id. As there is no other FDA-Approved
`therapeutic treatment for dry eye available on the US market, RESTASIS® owns 100%
`of the market share. Id.
`Aziz Mottiwala provides
`
`of
`the Declaration
`that
`Accordingly, the Applicants assert
`objective evidence that unequivocally establishes that the present invention as embodied
`in RESTASIS® has been met with commercial
`success.
`
`14
`
`0201
`
`

`
`Docket No. 17618CON5B (AP)
`
`The Claimed Methods Satisfied a Long-Felt Need
`As discussed during the Interview, the claimed methods also resolve a long-felt
`need for a therapeutic treatment for dry eye or keratoconjunctivitis sicca. In support of
`this position, the Applicants submit herewith as Exhibit 4, a Declaration of Dr. Rhett M.
`Schiffman under 37 C.F.R. § 1.132 (hereinafter, "Schiffman Declaration 2").
`According to the MPEP, establishing long-felt need requires objective evidence
`that an art recognized problem existed in the art for a long period of time without
`solution. See MPEP § 716.04.
`First, the need must have been a persistent one that was recognized by those of
`ordinary skill in the art. Id. As explained by Dr. Schiffman, dry eye/keratoconjunctivis
`sicca has been a known, persistent ocular disorder for many years. Publications on dry
`eye date back to at least the 1970's, and interest and publication on the subject has
`increased substantially since. See Schiffman Declaration
`2 2-4.
`
`at
`Second, the long-felt need must not have been satisfied by another before the
`invention by applicant. MPEP 716.04. As explained by Dr. Schiffman, no other
`therapeutic dry-eye drug has been approved by the FDA before or since RESTASIS®.
`See Schiffman Declaration 2 at ]{ 8. Other treatments for dry eye, such as artificial tears,
`have been commercially available, but they only exhibit a palliative effect, and do not
`See Schiffman
`work to increase tear production or otherwise treat the disease.
`Declaration 2 at ]{4.
`Third, the invention must in fact satisfy the long-felt need. MPEP 716.04. As
`shown by the FDA's
`approval of RESTASIS®
`and
`
`
`in praise the the industry discussed by
`
`Dr. Schiffman at paragraph 8 of Schiffman Declaration 2, the claimed methods have
`satisfied the long felt need. As explained above, RESTASIS® has been met with great
`commercial success, which further shows
`the
`
`satisfaction of the long felt need.
`for FDA
`Several other companies have tried
`to develop
`therapeutic
`drugs
`but many have failed. See Schiffman Declaration 2 at ]{ 9 and Exhibit N. The Federal
`Circuit has implicitly accepted
`that
`failure
`to
`obtain
`FDA
`approval
`is
`failure of others. Knoll Pharm. Co. v Teva Pharms. USA,
`Inc.,
`367
`F.3d
`Cir. 2004).
`
`1381,
`
`approval,
`
`relevant
`1385
`
`(Fed.
`
`15
`
`0202
`
`

`
`Docket No. 17618CON5B (AP)
`
`Accordingly, the Applicants assert that the second Declaration of Dr. Rhett M.
`Schiffinan provides objective evidence that unequivocally establishes that the present
`invention as embodied in RESTASIS® has satisfied a long felt need and that others have
`failed to meet such a long felt need.
`Hence, in view of the evidence presented above and presented in the attached
`declarations, the Applicants submit that the unexpected results, commercial success, and
`satisfaction of long felt need obtained from the claimed methods successfully rebut the
`prima facie case of obviousness presented in the Office Action. Thus, the Applicants
`respectfully request that the Examiner withdraw the outstanding rejections under 35
`U.S.C. § 103.
`
`day,
`
`Ding Teaches Away From the Claimed Method
`The Applicants also submit that a prima facie case of obviousness has not been
`established because Ding does not disclose or suggest administering an emulsion of
`0.05% cyclosporine and 1.25% castor oil
`at a frequency
`
`of as required by the twice a
`
`
`pending independent claims (i.e. 37. 54. and 60). Rather, Ding only discloses
`administration of emulsions, other than 0.05% cyclosporine and 1.25% castor oil, eight
`times a day for seven days. See Ding at col. 4, lines 31-44 and col. 5,
`lines 14-17.
`Moreover, the Applicants also submit that one of skill in the art at the time the
`invention was made would not have reduced the frequency of administration of the
`compositions disclosed in Ding from eight times a day
`to twice a day because Ding
`teaches away from such a modification. See MPEP
`§ 2145(X)(D).
`Notably, Ding discloses that therapeutic levels of cyclosporine were reached after
`0.40 wt%
`dosage of the Example compositions 1A-1D, which included between 0.10
`cyclosporin (higher than the currently claimed amount of cyclosporin). See Ding at col.
`5, lines 15-23.
`The Applicants submit that one of skill would not be motivated to
`decrease both the concentration of cyclosporin and the frequency of dosage in Ding, as
`such a modification may not reach therapeutic levels required for successful treatment
`with the drug.
`
`16
`
`0203
`
`

`
`Docket No. 17618CON5B (AP)
`
`Thus, at least for the reasons presented above, the Applicants respectfully request
`that the Examiner withdraw the outstanding
`rejections
`under
`35 U.S.C.
`§ 103.
`
`Obviousness-Type Double Patenting Rejection
`Claims 37-61 were rejected for non-statutory obvious-type double patenting in
`view of claims 1-8 of
`the Ding reference.
`The Applicants submit that the pending claims are patentably distinct from claims
`1-8 of Ding for at least the same reasons argued above. The Applicants respectfully
`request, therefore, that the Office withdraw the double patenting rejection of Claims 37­
`61 in view of claims 1-8 of Ding.
`
`Provisional Obviousness-Type Double Patenting Rejection
`Claims 37-61 were rejected for provisional non-statutory obvious-type double
`patenting in view of claims 37-60 of copending U.S. Patent Application No. 13/967,168,
`claims 37-60 of copending U.S. Patent Application No. 13/961,835, claims 37-61 of
`copending U.S. Patent Application No. 13/967,163, claims 37-61 of copending U.S.
`Patent Application No. 13/961,828, claims 37-60 of copending U.S. Patent Application
`No. 13/967,189, and claims 37-60 of
`copending U.S.
`Patent Application
`While the Applicants do not necessarily agree with the provisional non-statutory
`obviousness-type double patenting rejections recited above, in order to expedite
`prosecution, terminal disclaimers in the aforementioned applications were filed on
`October 7, 2013. Thus, the Applicants submit that the provisional obviousness-type
`double patenting rejection has been rendered moot and request that this provisional
`obviousness-type double patenting rejection be withdrawn.
`
`Provisional Statutory Double Patenting Rejection
`Claims 37-61 were rejected for statutory double patenting in view of claims 37-61
`Since this is a provisional
`of co-pending U.S. Patent Application No. 13/961,818.
`statutory double patenting rejection, the Applicants request that the Examiner allow the
`
`17
`
`No.
`
`13/961,808.
`
`0204
`
`

`
`Docket No. 17618CON5B (AP)
`
`present case to proceed to allowance over the other aforementioned case. See MPEP §
`804(2). The Applicants respectfully request, therefore, that the Office withdraw the
`provisional statutory double patenting
`rejection.
`
`Conclusion
`In view of the foregoing, the Applicants believe all claims now pending in the
`present application are in condition for
`allowance.
`The Commissioner is hereby authorized to charge any fees required or necessary
`for the filing, processing or entering of this paper or any of the enclosed papers, and to
`refund any overpayment, to deposit account 01-0885.
`If the Examiner believes a telephone conference would expedite prosecution of
`this application, please contact
`the undersigned
`at
`(714)
`246-6996.
`
`Date: October 14, 2013
`
`Respectfully submitted,
`
`/Laura L. Wine/
`
`Laura L. Wine
`Attorney of Record
`Registration Number 68,681
`
`Please direct all inquiries and correspondence
`Laura L. Wine, Esq.
`Allergan, Inc.
`2525 Dupont Drive, T2-7H
`Irvine, California 92612
`Tel: (714) 246-6996 Fax: (714)246-4249
`
`to:
`
`18
`
`0205
`
`

`
`EXHIBIT
`
`§§ §f{ H E§§ §f{ H E
`
`ET "3ET "3
`
`
`
`02060206
`
`0206
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`DECLARATION UNDER 37 C.F.R. 1.132
`
`of Dr. Rhett M. Schiffman,
`
`I, Rhett M. Schiffman, M.D., declare as follows:
`
`I have an M.D,
`Officer at Neurotech.
`I am currently a Vice President and Chief Medical
`Masters Degrees in Clinical Research Design and Statistical Analysis and in Health
`Services Administration, a Bachelor's degree in Bioengineering, and over 12 years of
`experience in the pharmaceutical industry at Allergan, Inc. ("Allergan"). I was also a
`clinical investigator in the Phase 3 studies for Restasis®. I am a co-inventor on several
`issued patents and pending applications related to treatment methods using ophthalmic
`products. My curriculum vita, which contains a list of my publications to which I
`contributed, is attached to this declaration as Exhibit A.
`
`2. I have been informed of the general nature of the rejections made by the Patent Office
`
`with respect to the previously presented claims of the above-referenced patent application
`and I am familiar with
`the references that the Patent Office has relied on in making these
`rejections. For example, I am aware of U.S. Patent No. 5,474,979 to Ding et
`al. ("Ding").
`
`3. Restasis® is an FDA approved product that is a commercial embodiment of the
`invention. Specifically, Restasis® is approved as a 0.05% by weight cyclosporin
`ophthalmic emulsion useful
`for the treatment of ophthalmic conditions, such as dry eye.
`Specifically, Restasis® ophthalmic emulsion is indicated to increase tear production in
`patients whose tear production
`is presumed to be suppressed due to ocular inflammation
`associated with keratoconjunctivitis
`sicca.
`
`4. I have reviewed the pending claims in the present application, and the pending claims
`cover the specific formulation of Restasis® and/or the approved methods of
`treatment of
`dry eye or keratoconjunctivitis sicca
`for Restasis®.
`
`5. In creating and testing the claimed methods and compositions, several unexpected
`
`benefits were discovered using the claimed compositions and/or claimed methods.
`
`for the treatment of dry eye disease or keratoconjunctivitis
`6. During development of a drug
`sicca, Allergan performed a randomized, multicenter, double-masked, parallel-group,
`dose-response controlled Phase 2
`trial on several cyclosporin-A and castor oil-containing
`formulations. In this Phase 2 study of moderate to severe KCS, the
`safety and efficacy of
`
`0207
`
`

`
`four cyclosporin A-containing emulsion compositions were compared to one another:
`0.05% by weight cyclosporin A with 0.625% by weight castor oil, 0.10% by weight
`cyclosporin A with 1.25% by weight castor oil, 0.20% by weight cyclosporin A with
`2.5% by weight castor oil, and 0.40% by weight cyclosporin A with 5.0% by weight
`castor oil. A vehicle containing 2.5% by weight castor oil was also tested and compared
`to these formulations. In this study, patients with moderate to severe dry eye disease were
`treated twice daily with one of the aforementioned cyclosporin A-containing
`formulations
`or a vehicle. All of the cyclosporin A-containing formulations as well as
`the vehicle also
`included 2.2% by weight glycerine, 1.0% by weight polysorbate 80, 0.05% by weight
`Pemulen, sodium hydroxide, and water. To the best of my knowledge, the specific
`cyclosporin-A containing formulations tested in humans in this Phase 2 study are
`disclosed in the Ding reference. Results from this study illustrating the change from
`baseline in corneal staining and change from baseline in Schirmer Score, key objective
`testing measures for dry eye or KCS, are shown in Exhibit B, Figures 1 and 2,
`respectively.
`
`7. As shown in Exhibit B, Figure 1, the 0.1% by weight cyclosporin A/ 1.25% by weight
`castor oil formulation demonstrated a
`greater decrease in corneal staining than
`the 0.05%
`by weight cyclosporin A/0.625% by weight castor oil formulation. As shown in Exhibit
`B, Figure 2 the 0.1% by weight cyclosporin A! 1.25% by weight castor oil formulation
`demonstrated a greater
`increase in Schirmer Score (tear production) at week 12 than any
`other formulation tested, including the 0.05% by
`weight cyclosporin A/0.625% by weight
`castor oil formulation. Corneal staining and Schirmer score are key objective measures
`for determining dry eye or keratoconjunctivitis
`sicca disease severity.
`
`8. After Allergan's Phase 2 study, Allergan initiated a Phase 3 study. In Allergan's
`multicenter, randomized, double-masked Phase 3 trials, Allergan compared the efficacy
`and safety of the formulation containing 0.10% by weight cyclosporin A and 1.25% by
`weight castor oil to a the claimed formulation (containing 0.05%
`by weight cyclosporin A
`and 1.25% by weight castor oil), and to a vehicle containing 1.25% by weight castor oil.
`The data presented in Exhibit B represents the subpopulation
`of moderate to severe Phase
`
`
`2 patients with the same reductions in tear production (<5 mm/5 min) as those enrolled in
`the Phase 3 studies. In this study, patients with moderate to severe dry eye disease were
`treated twice daily with either a formulation containing 0.10% by weight cyclosporin A
`and 1.25% by weight castor oil, a formulation containing 0.05% by weight cyclosporin
`and 1.25% by weight castor oil, or the vehicle. Both cyclosporin A-containing
`formulations and the vehicle also included 2.2% by weight glycerine, 1.0% by weight
`polysorbate 80, 0.05% by weight Pemulen, sodium hydroxide, and water.
`
`2
`
`0208
`
`

`
`9. I have reviewed the Declaration of Dr. Mayssa Attar ("Attar Declaration"), and I agree
`with her statements made in paragraphs 6-8, reproduced here.
`I have attached Exhibit B
`to the Attar Declaration to this Declaration as Exhibit C:
`
`10. "It was known in the art at the time this application was filed that cyclosporin could be
`administered topically locally to the eye to target and treat dry eye by using cyclosporin
`A's immunomodulatory properties to inhibit T cell activation which would lead to an
`
`increase in tear production and potentially other therapeutic
`effects related cyclosporine's
`anti-inflammatory and anti-apoptotic effects and thus limit chronic inflammation in the
`pathology of dry eye. To elicit it's therapeutic effect, cyclosporine must be effectively
`delivered to multiple target tissues of the ocular surface such as the cornea, conjunctiva,
`and lacrimal gland. The rate and extent at which cyclosporine is differentially delivered
`to the putative sites of action is critical to achieving therapeutic success in treating dry
`eye. Generally speaking, it was understood that pharmacokinetic/pharmacodynamic
`relationship would indicate that as more cyclosporin A reaches the target tissues of the
`ocular surface, such as the cornea and conjunctiva, the more immunomodulatory and
`more anti-inflammatory activity can take place and the more therapeutically effective a
`drug can be in treating dry eye.
`
`11. Pharmacokinetic studies were performed on animal eyes, which compared the
`pharmacokinetic properties of several cyclosporin A-containing formulations. Those
`results are attached to this declaration in Exhibit B. As shown in Exhibit B, the relative
`extent at cyclosporin was absorbed increased in the relevant ocular tissues, here, the
`cornea and the conjunctiva, where the amount of oil present in the formulation was
`decreased. Specifically, the amount of cyclosporin A that reached the relevant ocular
`tissue was higher for the formulation containing 0.05% by weight cyclosporin A and
`0.625% by weight castor oil than the formulation containing 0.05% by weight
`cyclosporin A and 1.25% by weight castor oil relative
`
`
`
`to the formulation containing 0.1%
`by weight cyclosporin A and 1.25% by weight castor oil.
`
`12. One of skill in the art would have understood such a result to mean that since there was
`more cyclosporin A present in the relevant ocular tissues in the formulation containing
`0.05% by weight cyclosporin A and 0.625% by weight castor oil and the formulation
`containing 0.1% by weight cyclosporine A and 1.25% by weight castor oil than the
`claimed formulation, that those formulations would have been more therapeutically
`effective than the claimed formulation. Specifically, this data suggests that the
`formulation containing 0.05% by weight cyclosporin A and 0.625% by weight castor oil
`
`would have been more therapeutically effective than the claimed formulation."
`
`0209
`
`

`
`13. Specifically, one of skill in the art would have expected patients receiving the claimed
`formulations and methods to exhibit a lesser decrease from baseline in corneal staining
`score and a lesser increase from baseline
`in Schirmer
`Score, relative to the patient corneal
`staining scores and Schirmer Scores demonstrated by the
`patients receiving the 0.05% by
`weight cyclosporin A / 0.625% by weight castor oil formulation (Ding
`IE) in the Phase 2
`trials illustrated in Exhibit B.
`
`14. Surprisingly, the claimed formulation and method was equally or more therapeutically
`effective for the treatment of dry eye/keratoconjunctivitis sicca than the formulation
`containing 0.10% by weight cyclosporin A and 1.25% by weight castor oil according to
`at least four testing parameters. This result was surprising and completely unexpected.
`
`These results are attached to this declaration in Exhibit D.
`
`15. As shown in the results in Exhibit D, the claimed formulation and method was
`unexpectedly superior to the 0.10% by weight cyclosporin A
`/ 1.25% by weight castor oil
`formulation with respect to several properties. For example, the claimed formulations
`and methods surprisingly exhibited a comparable or greater decrease in corneal staining
`score (see Exhibit D, Figure 1), a greater increase in Schirmer Score (see Exhibit D,
`Figure 2), an improvement in the common
`dry eye/keratoconjunctivitis sicca symptom
`of
`blurred vision (see Exhibit D, Figure 3) and a greater decrease in the number of artificial
`tears used by patients (see Exhibit D, Figure 4) compared to the formulation containing
`0.10% by weight cyclosporin A and 1.25% by weight castor oil.
`
`16. This result was even more surprising, given earlier testing from the Phase 2 study that
`illustrated that compositions containing 0.10% by weight cyclosporin A and 1.25% by
`weight castor oil provided more improvement in objective measures (such as corneal
`staining and increase in Schirmer Score - as illustrated in Exhibit B) in dry eye patients
`than compositions containing 0.05% by weight cyclosporin A and 0.625%
`castor oil.
`
`17.1 have compared the objective results showing the surprising therapeutic efficacy of the
`claimed formulation and method relative to the 0.10% by weight cyclosporin A and
`1.25% by weight castor oil formulation tested in Phase 3 to the 0.05% by weight
`cyclosporin A and 0.625% by weight castor oil formulation relative to the 0.10% by
`weight cyclosporin A and 1.25% by weight castor oil formulation tested
`in Phase 2. This
`comparison is attached to this declaration as Exhibit E.
`
`18. As seen in Exhibit E, in the Phase 2 study, the 0.05% by weight cyclosporin A/0.625% by
`weight castor oil formulation (Ding IE) only achieved 0.25 times the improvement in
`Schirmer Tear Test
`score as the 0.1 % by weight cyclosporin A/1.25% by weight castor
`
`4
`
`0210
`
`

`
`%
`oil formulation and only achieved 0.25 times the decrease in corneal staining as the 0.1
`
`
`
`by weight cyclosporin A/1.25% by weight castor oil formulation. However, in the Phase
`3 studies, the claimed formulation and method achieved twice the improvement in
`Schirmer Tear Test
`score as the 0.1 % by weight cyclosporin A/1.25% by weight castor
`oil formulation in the first study and substantially the same improvement in Schirmer
`Tear Test score as the 0.1 % by weight cyclosporin A/1.25% by weight castor oil
`formulation in the second Phase 3 study. Also, the claimed formulation achieved
`substantially the same decrease in corneal staining score compared to the 0.1 % by
`weight cyclosporin A/1.25% by weight castor oil formulation.
`
`19. As seen in Exhibit E, and further illustrated in Exhibit F, surprisingly, the claimed
`formulation and method demonstrated an 8-fold increase in relative efficacy for the
`Schirmer Tear Test Score in the first
`study of phase 3 compared to the 0.05% by weight
`cyclosporin A/0.625% by weight castor oil formulation (Ding Example IE) in the Phase
`2 study. Exhibits E and F also illustrate that the claimed formulations demonstrated a 4^
`fold improvement in the relative efficacy for the Schirmer
`Tear Test score for the second
`study of Phase 3 and a 4-fold
`increase in relative efficacy for decrease in corneal staining
`score in both of the Phase 3 studies compared to the 0.05% by weight cyclosporin
`A/0.625% by weight castor oil formulation in the Phase 2 study, the formulation
`disclosed in the Ding reference (Ding IE).
`This was clearly a very surprising result.
`
`20. Taking the results of these studies together, it is clear that the specific combination of
`0.05% by weight cyclosporin A with 1.25% by weight castor oil is surprisingly and
`unexpectedly critical
`for
`therapeutic effectiveness
`in
`the
`treatment of dry
`eye/keratoconjunctivitis sicca.
`
`5
`
`0211
`
`

`
`I hereby declare that all statements made herein of my own knowledge and belief are true;
`and that all statements made on information and belief are believed to be true; and further
`that these statements are made with the knowledge that willful false statements and the like
`so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of
`the United States Code, and that such willful false
`statements may jeopardize the validity of
`the application or any patents issued thereon.
`
`r
`//
`
`ftTkTr--
`^ M, Schiffman
`
`/&/////-%•
`
`-sv,J.
`
`•./.
`
`Date:
`
`0212
`
`

`
`EXHIBIT A
`
`EXHEET AEXHEET A
`
`
`
`02130213
`
`0213
`
`

`
`CURRICULUM VITAE FOR RHETT M. SCHIFFMAN, M.D., M.S., M.H.S.A.
`
`Current Title:
`
`Work Address:
`
`Home Address:
`
`Office Telephone:
`Cell Telephone:
`Email:
`
`EDUCATION:
`
`Professional:
`
`Undergraduate:
`
`Vice President and Chief Medical Officer
`Neurotech
`
`900 Highland Corporate Drive
`Building #1, Suite #101
`Cumberland, RI02864
`
`1843 Temple Hills
`Laguna Beach, CA 92651
`
`(401) 495-2395
`(313) 516-6924
`r.schiffman@neurotechusa.com
`
`University of Michigan, School of Public Health,
`Ann Arbor, Michigan
`2000 M.H.S.A. Health Services Administration
`
`University of Michigan, Rackham Graduate School,
`Ann Arbor, Michigan
`1989 M.S. Clinical Research Design & Statistical Analysis
`
`Universidad Autonoma de Ciudad Juarez
`Institute de Ciencias Biomedicas
`Juarez, Mexico
`1983 M.D. Medicine
`
`Columbia University
`School of Engineering and Applied
`New York, NY
`1978 B.S. Bioengineering
`
`Science
`
`POSTDOCTORAL TRAINING:
`
`Fellow:
`
`Resident:
`
`Resident:
`
`Intern:
`
`Uveitis and Ocular Immunology, National Eye Institute,
`National Institutes of Health, Bethesda, MD
`1996-1997
`
`Ophthalmology, Henry Ford Hospital, Detroit, Michigan
`1993 -1996
`
`Internal Medicine, Henry Ford Hospital, Detroit, Michigan
`1984 -1986
`
`Internal Medicine, Henry Ford Hospital, Detroit, Michigan
`1983 -1984
`
`0214
`
`

`
`Rhett M. Schiffman, M.D., M.S., M.H.S.A
`Page 2
`
`CERTIFICATION AND LICENSURE
`
`Medical Licensure: California, 2002 - C50825
`Michigan, 1983 - 4301046984
`Board Certification: American Board of Ophthalmology,
`1999; 93th percentile on Board examination
`
`American Board of Internal Medicine, 1986; 99,h percentile on Board examination
`
`PROFESSIONAL SOCIETIES:
`
`Member,
`
`Association for Research in Vision and Ophthalmology
`American Academy of Ophthalmology
`American Medical Association
`
`PROFESSIONAL EXPERIENCE:
`
`2013-Present
`
`Vice President and Chief Medical Officer, Neurotech
`
`2010-2013
`
`2009-2013
`
`2008-2013
`
`2007-2013
`
`2005-2013
`
`Board Member, Glaucoma Research Foundation
`
`Ophthalmology Therapeutic Area Head
`
`Head of Development for Emerging Markets
`
`Head, Global Product Enhancement/Life Cycle Management
`
`Vice President, Development for Ophtha Imology and Botox, Allergan
`Pharmaceuticals
`
`2003-Present
`
`Clinical Associate Professor and Attending Physician in Ophthalmology, University
`of California at Irvine.
`
`2001-2005
`
`1999-2001
`
`1999-2001
`
`1998-2001
`
`1997-2001
`
`1996-2001
`
`1999-2001
`
`Senior Director, Ophthalmology Clinical Research, Allergan Pharmaceuticals, Irvine,
`California
`
`Member, Leadership Council, Eye Care Services, Henry Ford Health System, Detroit,
`MI
`
`Director, Quality Improvement, Eye Care Services, Henry Ford Health System,
`Detroit, MI
`
`Director of the African-American Initiative for Male Health Improvement (AIMHI).
`Eye Disease Screening Program in Southeast Michigan. Funded by the Michigan
`Department of Community Health.
`
`Director of Uveitis Services, Eye Care Services, Henry Ford Health System, Detroit, MI
`Director of Clinical Research, Eye Care Services, Henry Ford Health System, Detroit, MI
`Staff Investigator, Center
`for Health Services Research, Henry Ford Health System,
`Detroit, MI
`
`Reviewer to Special Study Section, National Eye Institute, National Institutes of
`Health, Bethesda, Maryland.
`
`Director, Clinical Research, Eye Care Services, Henry Ford Hospital, Detroit,
`Michigan
`
`0215
`
`

`
`1996-1997
`
`1994-1995
`
`1993-2001
`
`1989-2001
`
`1988-1994
`
`1989-1993
`
`1990-1993
`
`Rhett M. Schiffman, M.D., M.S., M.H.S.A
`Page 3
`
`Senior Staff Physician, Eye Care Services, Ophthalmology, Henry Ford Health
`System, Detroit, Michigan (on intergovernmental personnel act to National Eye
`Institute, National Institutes of Health, Bethesda, Maryland)
`
`Associate Medical Director, Henry Ford Hospital Pharmacology Research Unit,
`Detroit, Michigan
`
`Associate Research Director, Eye Care Services, Henry Ford Hospital, Detroit,
`Michigan
`
`Staff, Center for Clinical Effectiveness, Henry Ford Hospital, Detroit, Michigan
`
`Requirements Advisory Committee to the Medical Information Management System,
`Henry Ford Hospital, Detroit, Michig