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`Part of the problem might reside with the requiatory processitself. The process for
`clearance of a new drug is complex and as the knowledge base concerning dry eye disease
`expands, the scientific basis for drug testing changes. According to Michael A. Lemp, MD,
`clinical professor at Georgetown and George Washington universities, "it was anticipated
`that the FDA would issue new guidelines forclinical trials in dry eye disease several years
`ago, but these have not been made public. The delay may rest with senior management
`within the Agency."
`
`The result is that there is no "one-stop shopping" source where would-be sponsors can learn
`the guidelinesfor clinical trial endpoints. Instead, sponsors must go to the FDA and make a
`proposal as to how they would performaclinical trial; the FDA reviews the proposal and
`informs the sponsor if it is acceptable, or which portions are acceptable or unacceptable.
`
`"While the FDA is quite open to these inquires and willing to listen to novel ap proaches,
`many times companies new tothis field feel as if they are guessing what the FDA wants,”
`Dr. Lemp explains. "They wonderif the FDA has changed whatis acceptable since the last
`time they heard. It's like trying to read the tea leaves."
`
`Chugging Along
`
`Despite the regulatory hurdles, some dry eye drugs are making slow but steady progress
`toward beleaguered physicians and their patients. Most are anti-inflammatories, so their
`approval would fulfill a wish of Dr. Trattler's. "I use pulses of topical steroids frequently for
`dry eye patients, and if there were additional anti-inflammatory drugs that could work in
`this area, that would be very heipful for patients, since dry eye is an inflammatory
`condition."
`
`® EGP-437. The closest drug to the goal is EyeGate's EGP-437. Currently in a phase 3
`efficacy study, it's a dexamethasonederived corticosteroid solution delivered to the eye via
`an iontophoretic drug delivery system that enables the drug to overcome the problem of low
`bioavailability that limits other topical agents. "You have to try to bypass natural barriers
`that are in place: the tear film and cornea," Mr. From says. "It's very difficult to get a large
`quantity of drug into the front of the eye, or any drug to the posterior pole of the eye for
`retinal diseases." Iontophoresis also allows EGP-437 to bypass the method physicians have
`had to resort to deliver large quantities of drug into the eye: needles.
`
`The doughnut-shaped applicator holds a sponge saturated with drug; the applicatoris
`placed on the sclera after a topical anesthetic is applied to prevent the patient's blinking. An
`electrode at the base of the applicator is connected to a small, handheld generator that
`supplies a charge. A negatively charged drug in the foam portion gets a negative charge to
`the electrode, thus using the principle of electrorepulsion to push the drug at a high velocity
`into the eye.
`
`The process, Mr. From says, requires only a couple of minutes. "Depending on how high the
`current is, or how long weleave this on the eye, will dictate how much drug goesinto the
`eye and how deepit penetrates into the eye."
`
`EGP-437 is a small molecule. In its recently-completed phase 2 study, it was able to treat
`multiple signs and symptomsof dry eye, rather than just one in each category, Mr. From
`says, "So we actually had the lucky advantage of being able to choose the best sign and the
`best symptom for our phase 3 trial." Even better, he says, was its onset of action, which
`begins within hours. "If you're a Sj6gren's patient and you have severe dry eye, you are ina
`lot of discomfort and pain" and at risk for scarring, Mr. From explains. Such patients would
`welcome a therapy with rapid onset of action. "No other drug that I'm aware of works as
`quickly as our drug is working," he says.
`
`Although data from EyeGate's 83-patient phase 2 trial are not yet available, the company
`did say that staining decreased in both fluorescein and lissamine green dyes, that
`conjunctival redness was reduced and that tear film breakup time increased.
`
`As for dosage, the drug would be administered in a physician's office, probably on a
`quarterly basis, according to Mr. From, depending on severity. The company has begun
`
`EXHIBIT 1004(Part 4 of 4)
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`Ophthalmology Management
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`
`enrolling patients for the phase 3 clinica! trial of approximately 180 planned. Mr. From
`anticipates that the trial should be completed during the first quarter of 2011, with top-line
`data available at the end of that period.
`
`He describes EyeGate's approach as acute therapy for a chronic problem. "We are able to
`put so much drug in so quickly to the tissues of the eye that we're knocking down the
`inflammatory cascade very rapidly. The drug doesn't stay in the eye very long, but the
`pharmacological effect lasts for a long time."
`
`@ CF101. Can-Fite BioPharma Ltd. recently opened an Investigational New Drug application
`(IND) with the FDA for a phase 3 study of its lead drug, CF101, for treatment of moderate
`to severe dry eye disease. Dr. Pnina Fishman, Can-Fite's CEO, says that CF101 exerts an
`anti-inflammatory effect and also an immunomodulatory one. The study will be initiated in
`few months.
`
`An earlier phase 2 study, in which CF101 wastaken orally as a monotherapy for 12 weeks,
`showedastatistically significant benefit in the clearing of fluorescein staining in the nasal,
`temporal, pupillary and inferior cornea, the company reports. CF101 also was found to be
`safe and well tolerated in the Phase 2. Further, the study showed a decrease in intraocular
`pressure in patients with dry eye, findings that have prompted Can-Fite toinitiate a phase 2
`clinical study for the drug's treatment of glaucoma.
`
`The randomized, double-masked phase3trial will compare two oral doses of CF101 to
`placebo. Approximately 240 patients will be enrolled at multiple centers, to be treated for 24
`weeks. The clinical endpoints are improvement of corneal fluorescein staining, tear
`production and dry eye symptom score.
`
`® Low-dose bromfenac. Ista Pharmaceuticals’ phase 2 trial of low-dose bromfenac
`(Remura) demonstrated improvementin both a key sign (lissamine green staining) and in
`symptoms (as measured by the Ocular Surface Disease Index) of dry eye in 38 patients
`over a six-week period. Further, patients treated with low-dose bromfenac maintained the
`improvementin signs and symptoms for 10 days after discontinuing treatment. The
`companyis currently in the processofinitiating the efficacy portion of the phase 3 program,
`which will entail two studies with a total of approximately 1,000 patients followed overa six-
`week period, according to Dr. Chandler. The safety portion of the phase3trial is tentatively
`scheduled to begin later this year and will comprise a six-month and a 12-monthtrial, with
`a total of approximately 4,000 patients.
`
`Dr. Chandler notes that low-dose bromfenac could address the impact of inflammation on
`the ocular surface, a central feature of dry eye. "Controiling inflammation could both quiet
`the symptoms — thatis, irritation, dryness, gritty, sandy feeling, burning in some cases —
`and improvethe signs, such as staining, of ocular surface disease," he explains. The
`approachyields a dual benefit, Dr. Chandler contends, because of bromfenac's efficacy in
`dealing with pain as well as its ability to interrupt the inflammatory cycle, thereby allowing
`the ocular surface to heal. "There are very few medications that truly address the
`inflammatory cascadethatis central to the disease while improving patient comfort,” he
`says.
`
`Although the inflammatory etiology of dry eye remains theoretical, Dr. Chandler says it does
`explain the results seen in the phase 2 open-labeltrial. Dr. Chandler contends that low-dose
`bromfenac has an onset of action that is "much faster" than the approximately eight weeks
`required for topical cyclosporine. In studies completed to date, he says, the drug produced a
`response rate that hovers around 70%.
`
`Regarding safety, Dr. Chandler points out that higher-dose bromfenac studied in more than
`1,600 patients did not result in any serious corneal adverse events; ocular adverse events
`observedin these studies resolved with no sequelae. From the perspective of global clinical
`experience with bromfenac, in about 19 million ophthalmic uses of the currently marketed
`higher concentration, there have been 22 serious corneal adverse events reported overall.
`Not all were considered drug related, Dr. Chandler points out, and most were in subjects
`who had undergonecataract surgery. "Lowering the concentration of bromfenac as we have
`done could further reduce the likelihood of severe corneal adverse events," he says. As part
`
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`Ophthalmology Management
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`Page 4 of 7
`
`of its commitment to patient safety, Ista has incorporated frequent monitoring of the cornea
`into the protocols for the large safety trials being planned.
`
`® SAR 1118. Sarcode Corp. says that the phase 2 results for SAR-118, a topical small-
`molecule lymphocyte function-associated antigen-1 antagonist, showed clear improvements
`in signs and symptomsof dry eye at 12 weeks. The trial was a randomized, multisite,
`doublemasked study involving 230 subjects. Various dose levels (0.1, 1.0 and 5.0%) were
`compared to placebo, with subjects receiving the drops BID for 12 weeks. The primary
`objective measure wasinferior corneal staining; major secondary measures were OSDI
`symptom score and tear production by Schirmer test. The companywill present full details
`of the phase 2 study in spring 2011. Sarcode is currently preparing for a phase 3 trial to
`begin in mid-2011.
`
`e Mapracorat. Bausch + Lomb is addressing the issue of tear hyperosmolarity in dry eye
`disease, which research suggests is a mechanism involved in ocular surface inflammation,
`with its selective glucocorticoid receptor agonist (mapracorat), currently in phase 2 trials. In
`vitro studies suggest mapracoratinhibits hyperosmolar-induced cytokine release and
`mitogenactivated protein kinase pathways in human corneal epithelial cells. Development of
`the compound continues to progress as a novel product with a new mechanism of action for
`the treatment of dry eye, according to B+L.
`
`A study in the September 2010 issue of Molecular Vision showed it to have comparable
`activity to dexamethasone in combating inflammation. The investigators evaluated
`mapracorat's anti-inflammatory effects in an in vitro osmotic stress model that induced
`hyperosmolar conditions in cultured human corneal cells. The model stimulated the release
`of pro-inflammatory cytokines interleukin-6, interleukin-8 and monocyte chemotactic
`protein-1, and also altered the phosphorylation state of p38 and c-Jun N-terminal kinase
`(JNK), and the transcriptional activity of NFkappaB and AP-1. The researchers found that
`the incubation of cells with mapracorat inhibited hyperosmolarinduced cytokine release with
`potency comparable to the dexamethasonecontrol group. Additionally, increased
`phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat,
`and the compound caused a significant decrease in the hyperosmolar-induced rise in
`NFkappaB and AP-1 transcriptional activity.
`
`® RX-10045. Oneof a class of medicines called resolvins, RX-10045 is a small-molecule
`lipid mediator that Resolvyx Pharmaceuticals says activates the body's own mechanismsfor
`shutting off inflammation. It is administered as a topical eye drop. Resolvyx completed a
`phase 2 trial last year for chronic dry eye. In the randomized, placebo-controlled, 232-
`patient trial, RX-10045 produced dose-dependent,statistically significant improvement on
`the primary endpoints for both the signs and symptomsof dry eye, and was generally
`shownto be safe and well tolerated, the company says.
`
`The phase 2 study examined three doses of RX-10045 and used a controlled adverse
`environment (CAE) simulator to measure corneal staining in a stressful drying environment,
`as well as daily patient diaries using a standard visual analog scale to assess symptom
`improvement overthe course of the 28-day study. The drug produced a significant
`dosedependent improvement from baseline in symptoms recorded in daily patient diaries. It
`also reduced staining of the central cornea by 75%(P<0.00001) versus placebo, the
`difference approaching statistical significance (P=0.11). Additionally, the drug showed a
`significant improvement in CAE-induced staining in the inferior cornea and in the composite
`of central and inferior cornea, which also approachedstatistical significance over placebo
`(P=0.09).
`
`Resolvyx says the phase 3 trial should begin by the end of the year.
`
`e AzaSite. Currently there is no prescription product indicated for blepharitis, a void Inspire
`Pharmaceuticals would like to fill with AzaSite (azithromycin). The drug is already approved
`as a treatment for bacterial conjunctivitis, but it did not meet statistically significant
`endpoints in two phase 2 trials for anterior blepharitis last spring. Though a four-weektrial
`did demonstrate improvement in measured signs and symptoms compared to placebo,
`statistical significance was not achieved for the primary endpoint of mean lid margin
`hyperemia.
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`
`On the secondary endpoints, however, Inspire president and chief executive officer Adrian
`Adams reports seeing some statistical significance in the areas of signs and symptoms. In
`the two-weektrial, there were nostatistically significant improvements for AzaSite
`compared to vehicle; this included the primary endpoint of clearing oflid debris.
`
`The companysaysit will use the data obtained from these studies to continue to develop
`trial parameters using AzaSite as a treatment for both anterior and posterior blepharitis,
`and expects to refine the trial design through the end of this year. The refinement will
`include study populations and "seeking improved mappability for assessing and measuring
`signs and symptoms," says Mr. Adams. "With that, we are looking to utilize the
`photographic reading centers to maximize thetrial.”
`
`Inspire anticipates completing the additional phase 2 AzaSite clinical work in 2011. The
`initiation of the phase 3 trial should begin sometime later next year.
`
`® LX-214. Lux Biosciences' dose-ascending phase 1 trial showed that LX-214, a novel
`topicai formulation of voclosporin, was well tolerated by healthy volunteers. There was no
`difference in tolerability between the vehicle control and the concentrations of drug tested
`(0.2% and 0.02%). In five subjects diagnosed with dry eye syndrome, the cohort "showed
`some improvementin their signs (measured by Schirmer's tear test) and symptoms
`(measured by the OSDI); most notably, the changes observed occurredin the relatively
`brief timeframe of the study, two weeks compared to what has been reported previously
`with cyclosporine emulsion," according to Dr. Anglade.
`
`Voclosporin affects the immune response at the surface of the eye, he explains. "We think
`by controlling the local inflam matory response, it will allow the tear-producing lacrimal
`gland and the surface of the eye to heal and improve tear production.
`
`LX-214 belongs to a class of agents knownascalcineurin phosphatase inhibitors, developed
`by the company into a nanomicellar formulation. "This renders LX214, a highly insoluble
`compound, a solution as opposed to an emulsion," Dr. Anglade explains. He believes the
`drug's solution formulation will help make it better tolerated than cyclosporine emulsion.
`
`Another advantage, says Dr. Anglade, is voclosporin's higher concentration. "A limitation of
`other forms of topical cyclosporine is that sufficiently high concentrations may not be
`achievedlocally. The ability to achieve high local concentrations may translate into
`improvedefficacy. We'll be able to assess that concept hopefully in the phase 3 when we do
`a large dose-ranging study."
`
`Dr. Anglade adds that the companyis planning a phase 2 proof-of-concept study for the
`near future.
`
`® Restasis X. Allergan reports thatit is currently testing a new variation of cyclosporine,
`Restasis X, in phase 2 clinical trials. The company is not able to speculate on expected
`timing for FDA approval.
`
`In related news, in a study published in the August issue of the British Journal of
`Ophthaimology, researchers evaluated the efficacy and safety of two concentrations (0.05%
`and 0.1%) of cyclosporine A in aqueous solution comparedto vehicle in treating the signs
`and symptomsof moderate-tosevere dry eye patients.’ At Day 21, the 1% group showed
`statistically significant improvement (p<0.05) in four symptoms and three ocular signs; the
`0.05% showedstatistically significant improvement in three symptoms and three signs; and
`the vehicle-only group in two symptoms and twosigns. According to the researchers, at Day
`42, the 0.1% group performed demonstrated improvementin four symptoms, while the
`0.05% group demonstrated improvementin one symptom and onesign.
`
`Hope for The Future
`
`Dr. Lemp's vantage point as a participant in many FDAtrials gives him reason to believe
`that the regulatory situation for dry eye drugs will soon improve. "As we learn more about
`the pathological processes at work in dry eye disease, new treatmentstrategies are
`emerging and data to support new endpoints are being published,” he notes.
`
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`Ophthalmology Management
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`Page 6 of 7
`
`For one thing, in a meeting earlier this year, the FDA's Wiley Chambers, MD, expanded the
`criteria for primary endpoints that the agency will accept, including studies that document a
`correlation between signs and symptoms. Included in that slide wasa list of inflammatory
`cytokines in the tears and tear osmolarity. "That's new,” says Dr. Lemp. "That's potentiaily
`big."
`
`Patient-reported outcomes are gaining favor with the FDA as well. The most common
`vehicle for reporting patient symptoms has been the 100-point scale OSDI. However,
`showing the required 29-point improvement in symptoms has been onerous. It has required
`sponsors to find patients who were highly symptomatic — "Who at least start out with 50 to
`60 points on the scale," Dr. Lemp says. "And that rules out 90%of the population with dry
`eye."
`
`New studies re-examining the relationships between subjective patient changes and levels
`of disease severity, novel ways to assess patient-reported improvement and a better
`understanding of the relationship between signs and symptomsin dry eye disease all have
`the potential to open the door to less onerous butscientifically rigorous study designs, Dr.
`Lernp notes. He believes that this augurs well for demonstration of clinical efficacy and the
`appearance of an expanded therapeutic portfolio of drugs for the more effective
`management of dry eye disease.
`
`Perhaps the best reason to believe that the fortunes of prescription dry eye drugswill
`improve? "Let's putit this way, to my knowledge, there are probably more than 30 drugsin
`the pipeline,” says Dr. Lemp. Many companies are investing in the dry eye market, and not
`just "the usual suspects” such as Alcon, Allergan and B+L.
`
`The fact that Restasis could generate an approximate half a billion dollars in revenue last
`year despite its demonstrated effect in only about 15%of the patients studied (according to
`the packagelabel), indicates significant unmet medical need and a healthy bottom line for
`those willing to invest.
`
`With industry on board and the FDA willing to updateits clinical trial criteria, the conditions
`for victories seem to be increasingly in place. OM
`
`Reference
`
`1. Baiza~-Duran L, Medrano-Palafox J, Herndndez-Quintela E, Lozano-Alcazar J, Alaniz-de la
`O JF. A comparative clinical trial of the efficacy of two different aqueous solutions of
`cyclosporine for the treatment of moderate-to-severe dry eye syndrome. Br J Ophthalmol.
`2010 Aug 1. [Epub ahead of print]
`
`Clinical Trial Pearis
`
`
`
`
`0422
`
`
`
`Ora, Inc. has been helping drug makers navigate clinical trials for 15 years, says George
`
`
`Ousier, director of the company's dry eye department, so they have a lot of experience in
`knowing what makes for a successful program. Here are his recommendations:
`® Identify proper inclusion/exciusion criteria. Because there are manydifferent
`
`
`causes of dry eye, and different medications that could potentially treat it, it is critical that
`
`
`companies take the time to match the medication's mechanism of action to the
`appropriate patient population.
`® Focus on both signs and symptoms. Related to proper inclusion criteria, it is
`
`
`necessary to only include patients who show both signs and symptomsof dry eye. "It
`
`sounds pretty straightforward, but there's actually a fair amount of lack of correlation
`
`between the two," Mr. Ousler says.
`
`
`® Design well-controlled studies and standardize. Certain clinical models enable
`better control for the endpoints of dry eye. Toward this end, Ora has developed the
`Controlled Adverse Environment (CAE). By controlling environmental factors such as
`humidity, temperature, air flow and visual tasking, "you can establish a screening tool to
`
`
`identify the right patient, and an endpoint to demonstrate efficacy.If it's better controlled,
`
`there's not so much background noise like traditional environmental studies," Mr. Ousler
`
`
`explains.
`
`
`
`
`
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`Ophthalmology Management
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`Page 7 of 7
`
`@ Reduce clinical sites. This helps to keep the trial well controlled and standardized.
`i@ Enlist the right crew. "It's more than just running a trial: you have to work with a
`ligroup of people who understand the disease as well as the entire clinical/requlatory
`
`Hpathway
`
`Ophthamoalogy Management, Issue: Novernber 2010
`
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`WIN
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`AAAS
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`INN
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`Inspire shelves dry-eye drug, shifts focus with Allergan - Triangle Business Journal
`
`Page 1 of 2
`
`From the Triangle Business Journal
`:http:/ /www.bizjournals.com/triangle/stories/2010/08/23/daily31.html
`
`Aug 25, 2010, 12:52pm EDT
`
`Inspire shelves dry-eye drug, shifts
`focus with Allergan
`
`Jeff Drew
`
`After a decade of development and disappointment, Inspire Pharmaceuticals finally has put
`a stop to its efforts to win U.S. Food and Drug Administration approval of a dry eye drug
`now called Prolacria.
`
`The Durham company on Wednesday unveiled a modified collaboration agreement with
`longtime partner Allergan (NYSE: AGN) that opens the wayfor Inspire to close the door on
`Prolacria and moveits focus to pink eye treatment AzaSite and the company’spromising
`
`Investors hailed the new agreement, pushing up Inspire shares by 3.88 percent, to $4.66, in
`mid-day trading Wednesday.
`
`Inspire twice sawits dry eye drug fail to outperform a placebo in the last stage of human
`testing. The company tried changing the drug’s name and adjusted the end point of the
`phaseIII clinical trial but endedupwiththesameresults.
`
`After studying the potential of moving forward with Prolacria, Inspire and Allergan were
`ready to move on. But the complicated nature of their drug development deal — which
`involves another dry eye treatment, Restasis — left Inspire facing a significant and
`immediate revenuehit.
`
`Inspire (Nasdaq; ISPH) receives royaities from Allergan on sales of Restasis and received
`payments from the Irish companyfor hitting development milestones on Prolacria. The
`previous termscalled for a 30 percent reduction in Inspire’s Restasis royalty rate of 7.5
`percentif the company dropped the Prolacria program and didn’t begin contributing to the
`marketing and promotion of Restasis.
`
`The new terms keep Inspire’s Restasis royalty rate unchanged at 7.5 percent for 2010,
`before reducing it by 3 percentage points in 2011, a further 0.25 percentage point in 2013,
`and a final 0.50 percentage point in 2014. The rate will remain at 3.75 percent until 2020,
`whenthe contract runs out.
`
`Restasis generated $11.2 million in royalty revenue for Inspire during the second quarter,
`which ended June 30. That was up from $8.9 million in the year-ago quarter.
`
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`Inspire shelves dry-eye drug, shifts focus with Allergan - Triangle Business Journal
`
`Page 2 of 2
`
`For the quarter, Restasis accounted for more than 40 percent of Inspire’s total revenue of
`$27.3 million and topped AzaSite, which produced revenue of $9.6 million.
`
`“This agreement provides clarity on the revenue stream and respective responsibilities of the
`parties in our ophthalmic collaboration,” said Adrian Adams, president and CEO of Inspire,
`which has 240 employees.
`
`Reporter e-mail: jdrew@bizjournals.com
`
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`Electronic Acknowledgement Receipt
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`17119376
`
`13967 168
`
`Application Number:
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`International Application Number:
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`Confirmation Number:
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`Utility under 35 USC 111)
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`Title of Invention:
`
`First Named Inventor/Applicant Name:
`
`Andrew Acheampong
`
`Customer Number:
`
`51957
`
`Laura Lee Wine/Alexis Swan
`
`Filer Authorized By:
`
`Laura Lee Wine
`
`Attorney Docket Number:
`
`17618CON7B (AP)
`
`Receipt Date:
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`14-OCT-2013
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`New Applications Under 35 U.S.C. 111
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`If a new international application is being filed and the international application includes the necessary componentsfor
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/105)will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this AcknowledgementReceiptwill establish the international filing date of
`
`0431
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`

`PTO/SB/06 (09-11)
`Approvedfor use through 1/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unlessit displays a valid OMB control number.
`
`PATENT APPLICATION FEE DETERMINATION RECORDJ4pplication or Docket Number Filing Date
`
`Substitute for Form PTO-875 08/14/2013|CI Tobe Mailed13/967,168
`
`
`
`ENTITY:
`
`[X)LaRGe [] smact [] micro
`
`APPLICATION AS FILED — PART|
`
`(Column 1)
`
`NUMBER FILED
`
`(Column 2)
`
`NUMBER EXTRA
`
`37 CFR 1.16(a),
`
`(b), or
`
`(c
`
`37 CFR 1.16(k),
`
`(i), or
`
`(m
`
`CL EXAMINATION FEE
`
`TOTAL CLAIMS
`37 CFR 1.16(i
`INDEPENDENT CLAIMS
`37 CFR 1.16(h
`
`LIJAPPLICATION SIZE FEE
`(37 CFR 1.16(s))
`
`.
`
`.
`
`APPLICATION AS AMENDED - PARTII
`
`(Column 1)
`
`(Column 2)
`
`(Column 3)
`
`AMENDMENT
`
`PAID FOR
`
`PRESENTEXTRA
`
`ADDITIONALFEE($)
`
`j
`minus 20 =
`J
`minus 3 =
`If the specification and drawings exceed 100 sheets
`of paper, the application size fee due is $310 ($155
`for small entity) for each additional 50 sheets or
`fraction thereof. See 35 U.S.C. 41(a)(1)(G) and 37
`CFR 1.16(s).
`[_] MULTIPLE DEPENDENT CLAIM PRESENT(37 CFR 1.16()))
`* If the difference in column 1 is less than zero, enter “O” in column 2.
`
`The “Highest Number Previously Paid For’ (Total or Independent) is the highest numberfound in the appropriate box in column 1.
`
`CLAIMS
`
`HIGHEST
`
`hereNG S| SREYOUSLY
`
`AMENDMENT
`
`AMENDMENT
`
`C Application Size Fee (37 CFR 1.16(s))
`
`Cc FIRST PRESENTATION OF MULTIPLE DEPENDENTCLAIM (37 CFR 1.16(j))
`
`(Column 1)
`
`CLAIMS
`REMAINING
`AFTER
`AMENDMENT
`*
`
`Total (37 CFR
`Total
`(37 GFR 1.16(h))
`[_] Application Size Fee (37 CFR 1.16(s))
`
`i
`Minus
`
`(Column 3)
`
`PRESENT EXTRA
`
`(Column 2)
`
`HIGHEST
`NUMBER
`PREVIOUSLY
`PAID FOR
`
`**
`
`Cc FIRST PRESENTATION OF MULTIPLE DEPENDENTCLAIM (37 CFR 1.16(j))
`
`* |f the entry in column 1 is less than the entry in column 2, write “O” in column 3.
`** If the “Highest Number Previously Paid For’ IN THIS SPACEis less than 20, enter “20”.
`*** If the “Highest Number Previously Paid For’ IN THIS SPACEis less than 3, enter“3”.
`
`LIE
`/EVELYN NIMMONS/
`
`This collection of information is required by 37 CFR 1.16. The information is required to obtain or retain a benefit by the public whichis to file (and by the USPTOto
`process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 12 minutes to complete, including gathering,
`preparing, and submitting the completed application form to the USPTO. Time will vary depending uponthe individual case. Any comments on the amountof time you
`require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office, U.S.
`Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMSTO THIS
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`If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
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`0432
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`

`

`Docket No. 17618CON7B (AP)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant: Acheampong,etal.
`
`Examiner: Marcela M Cordero Garcia
`
`Serial No.: 13/967,168
`
`Group Art Unit: 1658
`
`Filed: August 14, 2013
`
`Confirmation No. 3265
`
`For: METHODS OF PROVIDING
`THERAPEUTIC EFFECTS USING
`
`CYCLOSPORIN COMPONENTS
`
`Customer No.: 51957
`
`INTERVIEW SUMMARY
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`DearSir:
`
`Attached herewith please find an interview summary.
`
`Summary ofthe Interview beginsat page 2.
`
`0433
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`

`

`Docket No. 17618CON7B (AP)
`
`Attendees, Date and Type of Interview
`
`SUMMARYOF INTERVIEW
`
`A telephone interview was conducted on November7, 2013 and was attended by
`
`Examiner Cordero Garcia and Laura L. Wine.
`
`Identification of Claims Discussed
`
`The Claims were discussed.
`
`Identification of Prior Art Discussed
`
`U.S. Patent Application Publication No. 2005/0014691 (U.S. Application Serial
`
`No. 10/621,053, “the ‘691 Publication’’) was discussed.
`
`Principal Arguments and Other Matters
`
`The Applicants presented arguments that the ‘691 Publication did not discloseall
`
`claimed limitations. The Applicants also argued that a rejection under 35 U.S.C. 103(a)
`
`would be improper because the “691 publication should be disqualified under 35 U.S.C.
`
`103(c) because the present application (US 13/967,168) and the ‘691 publication, at the
`
`time the invention of