IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Serial No.:
`
`Ashley, Robert
`
`13/277,789
`
`Confirmation No:
`
`4179
`
`Filed:
`
`For:
`
`October 20, 2011
`
`Methods of
`Treating Acne
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`Examiner:
`
`Susan Tran
`
`Group Ati Unit:
`
`1615
`
`Docket:
`
`Dated:
`
`512-53 DIV/CON II
`
`September 19, 2012
`
`Certificate ofEFS-Web Transmission
`I hereby certify that this correspondence is being transmitted to the
`United States Patent and Trademark Office via the Office's electronic
`filing system on September 19. 2012
`
`Printed Name: "='Car"""'la'""B'-'"tyuan""------------
`Signature: /carla btyan/
`
`Response to May 14,2012 Office Action
`
`Sir:
`
`In Response to May 14, 2012 Office Action, Applicant respectfully requests the
`instant Amendment be entered.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 5 of this paper.
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1070
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 2 of 18
`
`Listing of the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application.
`
`Claims 1-20 (Cancelled).
`
`21. (Previously Presented) A method for treating papules and pustules of rosacea in a
`human in need thereof, the method comprising
`administering orally to said human doxycycline, or a pharmaceutically acceptable salt
`thereof,
`in an amount that
`(i) is effective to treat the papules and pustules of rosacea;
`(ii) is 10-80% of a 50 mg dose of doxycycline; and
`(iii) results in no reduction of skin microflora during a six-month treatment, without
`administering a bisphosphonate compound.
`
`22. (Previously Presented)
`doxycycline monohydrate.
`
`The method according to Claim 21, wherein said doxycycline is
`
`The method according to Claim 22, wherein said doxycycline
`23. (Previously Presented)
`monohydrate is administered in an amount of 40 milligrams.
`
`The method according to Claim 23, wherein said doxycycline
`24. (Previously Presented)
`monohydrate is administered by sustained release.
`
`25. (Previously Presented) A method according to Claim 24, wherein said doxycycline
`monohydrate is administered once a day.
`
`The method according to Claim 22, wherein said doxycycline
`26. (Previously Presented)
`monohydrate is administered in a dose of 20 mg twice a day.
`
`2
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 3 of 18
`
`The method according to Claim 21, wherein said doxycycline,
`27. (Previously Presented)
`or a pharmaceutically acceptable salt thereof, is administered in an amount which provides a
`serum concentration in the range of about 0.1 to about 0.8 11g/ml.
`
`28. (Previously Presented) A method for treating papules and pustules of rosacea in a
`human in need thereof, the method comprising
`administering orally to said human doxycycline, or a pharmaceutically acceptable salt
`thereof,
`in an amount that
`(i) is effective to treat the papules and pustules of rosacea;
`(ii) is 40-80% of a 50 mg dose of doxycycline; and
`(iii) results in no reduction of skin microflora during a six-month treatment, without
`administering a bisphosphonate compound.
`
`29. (Previously Presented)
`doxycycline monohydrate.
`
`The method according to Claim 28, wherein said doxycycline is
`
`The method according to Claim 29, wherein said doxycycline
`30. (Previously Presented)
`monohydrate is administered in an amount of 40 milligrams.
`
`The method according to Claim 30, wherein said doxycycline
`31. (Previously Presented)
`monohydrate is administered by sustained release.
`
`32. (Previously Presented) A method according to Claim 31, wherein said doxycycline
`monohydrate is administered once a day.
`
`The method according to Claim 29, wherein said doxycycline
`33. (Previously Presented)
`monohydrate is administered in a dose of 20 mg twice a day.
`
`3
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 4 of 18
`
`The method according to Claim 28, wherein said doxycycline,
`34. (Previously Presented)
`or a pharmaceutically acceptable salt thereof, is administered in an amount which provides a
`serum concentration in the range of about 0.1 to about 0.8 11g/ml.
`
`35. (Previously Presented) A method for treating papules and pustules of rosacea in a
`human in need thereof, the method comprising
`administering orally to said human doxycycline, or a pharmaceutically acceptable salt
`thereof, in an amount of 40mg per day, wherein the amount results in no reduction of skin
`microflora during a six-month treatment, without administering a bisphosphonate compound.
`
`36. (Previously Presented)
`doxycycline monohydrate.
`
`The method according to Claim 35, wherein said doxycycline is
`
`The method according to Claim 36, wherein said doxycycline
`37. (Previously Presented)
`monohydrate is administered by sustained release.
`
`38. (Previously Presented) A method according to Claim 37, wherein said doxycycline
`monohydrate is administered once a day.
`
`The method according to Claim 36, wherein said doxycycline
`39. (Previously Presented)
`monohydrate is administered in a dose of 20 mg twice a day.
`
`The method according to Claim 35, wherein said doxycycline,
`40. (Previously Presented)
`or a pharmaceutically acceptable salt thereof, is administered in an amount which provides a
`serum concentration in the range of about 0.1 to about 0.8 11g/ml.
`
`4
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 5 of 18
`
`RE MARKS
`
`Claims 1-20 were previously cancelled. Claims 21-40 were previously added. Thus,
`Claims 21-40 are pending.
`
`The Claimed Invention
`
`Pending Claims 21, 28 and 35 are independent. Theseclaims recite a method for
`treating papules and pustules of rosacea by oral administration of doxycycline ( or a salt
`thereof). Papules and pustules occur on skin in facial rosacea. The dose is expressed
`differently in each independent claim. The dose recited in Claim 21 is 10-80% of a 50 mg
`dose of doxycycline. The dose recited in Claim 28 is 40-80% of a 50 mg dose of
`doxycycline. The dose recited in Claim 35 is 40 mg. The claims recite that all these doses
`result in no reduction of skin microflora during a six-month treatment
`
`Applicant takes this opportunity to elaborate on the disease of rosacea. There are four
`sub-types ofrosacea. Rosacea patients can have any one, or occasionally more than one, of
`these sub-types. One sub-type affects the eyes and is called ocular rosacea. Another sub-
`type is characterized by papules and pustules, and is called herein facial rosacea. 1 Ocular
`rosacea and facial rosacea are distinct medical conditions. 2
`
`1 The National Rosacea Society assembled a committee to develop a standard classification system ofrosacea.
`Their report, authored by Wilkin et al., appeared in J. Am. Acad. Dermatol. 46, 584-587 (2002), and is attached
`as ExhibitA. This authoritative report identified four specific sub-types ofrosacea. Subtype 2 is called
`"papulopustular rosacea," and is characterized by transient papules and/or pustules. Subtype 4 is called "ocular
`rosacea," and is characterized by ocular manifestations.
`
`2
`(a) In addition to evidence provided in footnote 1, facial rosacea and ocular rosacea are treated by
`physicians in different specialties with different Board certifications, i.e., dermatologists and ophthalmologists,
`respectively.
`(b) Moreover, the agency that approves drugs in the United States, namely the Center for Drug
`Evaluation and Research (CDER) ofthe Food and Drug Administration, evaluates drugs for facial rosacea and
`ocular rosacea in different divisions. Facial rosacea is evaluated in the Division of Dermatologie and Dental
`Products. Ocular rosacea is evaluated in the Division of Anti-Infection and Ophthalmologie Products. For the
`examiner's convenience, a 2006 chart ofthe organization ofthe CDER showing theseparate divisions of
`Dermatologie and Dental Products and of Anti-Infection and Ophthalmologie Products is attached as Exhibit B.
`
`5
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 6 of 18
`
`In particular, papules and pustules are inflammatory lesions that occur only on skin.
`They do not occur in the eye. See, e.g., the following definitions from www.medterms.com.
`
`"Papules: Small solid rounded bumps rising from the skin that are each usually less
`than 1 centimeter in diameter (less than 3/8 inch across ). . .. "
`
`"Pustule: A pustule is a small collection of pus in the top layer of skin ( epidermis) or
`beneath it in the dermis. Pustules frequently form in sweat glands or hair follicles .... "
`
`See, also, www.nlm.nih.gov/medlineplus/encyclopedia.html.
`"A papule is a skin lesion that is small, solid, and raised."
`
`"Pustules are small, inflamed, pus-filled, blister-like lesions on the skin surface."
`
`The definitions from the above websites are attached as Exhibit C.
`
`Accordingly, it is clear that papules and pustules are features of facial rosacea, but not
`of ocular rosacea. Therefore, the claimed method, by its terms, requires the treatment of
`facial rosacea, but not of ocular rosacea. That is, there is no ocular component of rosacea in
`the pending claims since papules and pustules do not occur in the eye.
`
`Obviousness Rejection under §103(a) in View of Perricone and Pflugfelder
`
`The examiner rejects Claims 21, 23, 25-28, 30, 32-35 and 38-40 under §103(a) as
`allegedly being obvious over US 6,365,623 (hereinafter "Perricone") in view ofUS
`6,455,583 (hereinafter "Pflugfelder"). (Office Action pages 2-3.)
`
`In particular, the examiner alleges that Perricone teaches the treatment of pustules
`and papules with oral administration of an antibiotic compound. The examiner concedes that
`Perricone does not teach a specific amount of an antibiotic compound, does not teach
`doxycycline, and does not teach rosacea. In an attempt to overcome the deficiencies in
`Perricone, the examiner cites Pflugfelder for teaching "a method for treating conditions
`associated with rosacea ... [ comprising] orally administering a tetracycline compound in a
`sub-antimicrobial amount. .. "
`
`6
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 7 of 18
`
`The examiner alleges that it would have been obvious "to optimize the method of
`Perricone to administer antibiotic compound in a sub-antimicrobial amount in view of the
`teachings of Pflugfelder." Applicant respectfully disagrees with the examiner's analysis, as
`discussed below.
`
`Perricone teaches treatment of skin with lipoic acid and antibiotics
`
`Perricone teaches that lipoic acid can be topically applied to the faces of persons with
`acne ( col. 8, lines 6-1 0). In some embodiments, lipoic acid may be used "in combination
`with" antibiotic tetracycline to treat papules and pustules of acne ( col. 8, lines 24-30).
`
`As the examiner indicates, Perricone does not teach an exact amount of antibiotic
`tetracycline to be administered. However, Perricone does specifically instruct that an
`antibiotic amount be used in its treatment. In particular, Perricone states:
`
`Lipoic acid may be added to an antibiotic preparation, or applied before, during,
`or after antibiotic treatment ... [ A ]n advantage of using lipoic acid with antibiotics
`in cases where they might be efficacious is that a lower antibiotic dose or a
`shorter antibiotic reg1men may be employed.
`(See col. 8,
`lines 27-32.)
`(Emphasis added.)
`
`Perricone mentions the potential adverse effects of the use of antibiotic compounds,
`including tetracycline, clindamycin and erythromycin, and states that it may be advantageaus
`to minimize antibiotic doses. However, Perricone does not state that any dose but an
`antibiotic dose is effective in treating acne. The method of Perricone requires an antibiotic
`dose. A minimum antibiotic dose is still an antibiotic dose.
`
`7
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 8 of 18
`
`To elaborate, as would be known to a skilled artisan, at a certain threshold dose,
`tetracycline exhibits antibiotic properties. Depending on various factors, including the
`severity of an ailment, a physician may prescribe tetracycline at a dose that is weil above the
`antibiotic threshold dose, at a minimum antibiotic dose, or at a dose somewhere in between
`such doses. (For example, Exhibit H, attached, is a page from the wwvv.pdrhealth.com
`showing that tetracycline is commonly prescribed from a dose of 1 to 2 grams per day.)
`Nonetheless, above a threshold dose, tetracyclinewill be an antibiotic dose.
`
`In summary, Perricone teaches treating facial acne with the topical application of
`lipoic acid in combination with the oral administration of an antibiotic dose of tetracycline.
`Thus, there is no suggestion of treating acne (let alone treating the papules and pustules of
`rosacea) with a dose other than the commonly prescribed antibiotic dose of any tetracycline
`compound (let alone doxycycline ). The method of Perricone reguires an antibiotic dose.
`
`In an attempt to overcome the deficiencies in Perricone, the examiner cites
`Pflugfelder. However, as discussed below, Pflugfelder cannot be properly combined with
`Perricone in a way that Ieads to the presently claimed method.
`
`Pflugfelder teaches treatment of the eye for a disease of the eye
`
`The examiner states that Pflugfelder teaches "a method for treating conditions
`associated with rosacea." The condition that Pflugfelder teaches treating is an eye condition,
`i.e., meibomian gland disease. See the title and column 2, line 21 et seq.
`
`According to Pflugfelder, meibomian gland disease is a "tear film and ocular surface
`disorder." Symptoms include "blurred or filmy vision, burning or foreign body sensations in
`the eye, photophobia, and pain" and patients' "meibomian glands can atrophy." (See col. 1,
`lines 8-10 and 19-23.)
`
`8
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 9 of 18
`
`The treatment of a patient having meibomian gland disease is described in Pflugfelder
`as follows:
`
`According to the subject invention, treatment of a patient having meibomian
`gland disease includes reducing or reversing irritation symptoms, delayed tear
`clearance, recurrent corneal epithelial erosion or aqueous tear deficiency. (Col. 3,
`lines 39-42.)
`
`All ofthese manifestations ofmeibomian gland disease relate to the eye. That is,
`meibomian gland disease is an ailment that solely affects the eye. Accordingly, a person
`having ordinary skill in the art would understand Pflugfelder as disclosing the use of
`tetracyclines to treat the eye.
`
`There is no disclosure or suggestion in Pflugfelder of treating any condition or
`symptom outside of the eye. There is no disclosure of treating any facial condition in
`Pflugfelder, Iet alone treating the papules and pustules of facial rosacea.
`
`It is true, as noted by the examiner, that Pflugfelder discloses an association between
`meibomian gland disease and rosacea. There is, however, no discussion in Pflugfelder ofthe
`nature of the association. Moreover, the alleged "association" between meibomian gland
`disease and rosacea does not suggest a treatment for rosacea. Meibomian gland disease is not
`rosacea, and certainly not facial rosacea. Meibomian gland disease is a distinct clinical
`disorder.
`
`Further, whenever Pflugfelder mentions rosacea, the focus is exclusively on
`meibomian gland which are, anatomically and functionally, organs ofthe eye. 3 A skilled
`artisan would clearly understand, therefore, that the rosacea with which Pflugfelder reports
`
`3 Meibomian glands are sebaceous glands that occur only on the rim ofthe eyelids, and are responsible for the
`supply to the eye of sebum, an oily substance that, inter alia, prevents evaporation ofthe eye's tear film. They
`do not appear anywhere in the body except on the rim ofthe eyelids, and have no fi.mction outside ofthe eye. A
`discussion and diagram showing the location ofmeibomian glands is shownon a page from Gray's Anatomy,
`which is attached as Exhibit D. (Emphasis added.)
`
`9
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 10of18
`
`meibomian gland disease is somehow associated is ocular rosacea. There is no suggestion
`that Pflugfelder contemplates treating facial rosacea.
`
`The disclosures in Pflugfeldersupport this conclusion. For example, the phrase
`"meibomian gland disease associated with rosacea" is found twice in the "Detailed
`Description of the Invention" section of Pflugfelder. The first occurrence of the phrase is
`found in the paragraph bridging columns 3 and 4. There, a person having ordinary skill
`learns that the activity of gelatinase B " ... is markedly increased in the tear fluid of patients
`with meibomian gland disease associated with rosacea," and that the " ... activity of
`gelatinase B appears tobe inversely correlated with tear clearance." A person having
`ordinary skill would conclude from these statements about the composition and clearance of
`tears that meibomian gland disease is associated with ocular rosacea.
`
`In the next paragraph, Pflugfelder states explicitly that the rosacea contemplated is
`ocular rosacea. See column 4, lines 5-10, especially line 9, where Pflugfelder refers to
`certain factors "that have been found to be strongly correlated with the development of
`ocular rosacea in our studies." (Emphasis added. ).
`
`Pflugfelder again uses the phrase "meibomian gland disease associated with rosacea"
`in the Detailed Description ofthe Invention section at column 4, line 17 et seq. There,
`Pflugfelder discloses treating meibomian gland disease associated with rosacea by topical
`administration of a tetracycline analogue in an ointment or in solution ( e.g., "eye drops").
`See column 4, line 17. A person having ordinary skill would understand a topical treatment
`ofthe eye as being for ocular symptoms.
`
`That the phrase "meibomian gland disease associated with rosacea" refers to ocular
`rosacea is confirmed by the use ofthe same phrase in example 5 at column 8, line 55 et seq.
`of Pflugfelder. Example 5 discloses the treatment of eleven patients with "meibomian gland
`disease associated with rosacea." The treatment included " ... topical administration to the
`ocular surface or the eyelids" of oxytetracycline. See column 8, line 64. Table 2 at the top of
`
`10
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 11 of 18
`
`column 9 summarizes the results of the experiment in example 5 of Pflugfelder. The title of
`table 2 is "Patients with Ocular Rosacea Treated with Oxytetracycline Ointment 1."
`(Emphasis added.)
`
`A person having ordinary skill would understand that treatment of meibomian gland
`disease by topical administration "to the ocular surface or the eyelids" means treating the eye.
`Clearly, suchtreatmentwill not affect papules and pustules of facial rosacea. The
`unexplained association between meibomian gland disease and ocular rosacea reported in
`Pflugfelder is, therefore, not relevant to the teachings of Perricone which are directed to
`treating facial acne.
`
`No reason to combine Perricone and Pflugfelder
`
`The examiner summarizes the obviousness rejection over Perricone in view of
`Pflugfelder as follows:
`[I]t would have been obvious to one of ordinary skill in the art ... to optimize the
`method of Perricone to administer antibiotic compound in a sub-antimicrobial
`amount in view of the teaching of Pflugfelder. (See the sentence bridging pages 2
`and 3 of the Office Action.)
`
`The examiner proposes three reasons for combining the disclosure relating to treating
`facial acne in Perricone with the disclosure relating to treating meibomian gland disease in
`Pflug{elder. These reasons do not justify the combination.
`
`As a first reason, the examiner alleges, "Pflugfelder teaches the use of an antibiotic
`compound for the treatment ofrosacea related conditions known in the art." (See the
`paragraph bridging pages 2 and 3 of the Office Action.)
`
`11
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 12 of 18
`
`However, as explained in detail above, Pflugfelder simply teaches treating an ocular
`disorder. There is no suggestion whatsoever in Pflugfelder to treat a skin condition.
`Whereas, Perricone simply teaches treatment of a facial skin condition. There would be no
`reason for a skilled artisan to believe that a treatment that is effective to treat an ocular
`disorder would treat a skin condition. Medicine is much too unpredictable for such
`conjecture. Thus, a skilled artisan would have no reason to combine the two references.
`
`As the second reason for combining the disclosures, the examiner states that
`Pflugfelder teaches that "long term administration of antibiotic compound in a sub-
`antimicrobial amount will minimize adverse side effects ... " As the third reason, the
`examiner states that Perricone "teaches the desirability for administering antibiotic
`compounds in a lower dosage amount to eliminate adverse side effects ... "
`
`Applicant respectfully asserts that Pflugfelder 's teaching that a sub-antibiotic dose of
`a tetracycline compound is useful to treat ocular disorders is irrelevant to the method of
`Perricone. It is irrelevant for at least three reasons:
`i) Perricone teaches treating a different ailment than Pflugfelder (i.e., facial acne vis-
`a-vis meibomian gland disease );
`ii) Perricone teaches treating a different organ ofthe body than Pflugfelder (i.e., skin
`vis-a-vis the eye ); and
`iii) Perricone specifically indicates that an antibiotic dose is necessary to treat facial
`skin acne.
`
`Accordingly, although a skilled artisan may believe that a sub-antibiotic dose of
`tetracycline may lead to fewer side effects, the skilled artisan would have no reason to
`believe that such sub-antibiotic dose would be effective in the method of Perricone (Iet alone
`"optimize" treatment).
`
`12
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 13 of 18
`
`In summary, a skilled artisan would not combine a reference directed to treating facial
`acne with an antibiotic dose of tetracycline with a reference directed to treating an ocular
`disorder with sub-antibiotic doses. Accordingly, withdrawal ofthe obviousness rejection is
`respectfully requested.
`
`Obviousness Rejection under §103(a) in View of Perricone, Pflugfelderand Sheth
`
`The examiner rejects Claims 24, 25, 31, 32,37 and 38 under §103(a) as allegedly
`being obvious over Perricone, Pflugfelder, and US 5,300,304 (hereinafter "Sheth"). (Office
`Actionpage 3.) These dependent claims recite sustained release of doxycycline and/or
`release over a 24 hour period. The examiner cites Sheth for allegedly teaching a once a day
`sustained release dosage of a tetracycline compound for treating acne.
`
`Since the rejected dependent claims have a narrower scope than the independent
`claims, the dependent claims are patentable for at least the same reasons as the independent
`claims are patentable, as discussed above.
`
`Obviousness Rejection under §103(a) in View of Perricone, Pflugfelderand Heesch
`
`The examiner rejects Claims 22, 29 and 36 under §103(a) as allegedly being obvious
`over Perricone, Pflugfelder, and U.S. Patent Application Publication No. 2002/0165220
`(hereinafter "Heesch"). (Office Actionpage 4.) These dependent claims recite a doxycycline
`monohydrate. The examiner cites Heesch for allegedly teaching that doxycycline hyclate has
`advantages over doxycycline (para. [0093] of Heesch ).
`
`Since the rejected dependent claims have a narrower scope than the independent
`claims, the dependent claims are patentable for at least the same reasons as the independent
`claims are patentable, as discussed above.
`
`13
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 14 of 18
`
`Secondary Considerations Further Support Patentability of the Present Claims
`
`Applicant believes that the present claims are not prima facie obvious over the cited
`prior art alone or in combination for all the reasons above. Even if, for argument's sake, a
`proper primafacie obviousness rejection had been made out, it would be clearly rebutted by
`secondary considerations.
`
`The use of antibiotic amounts of tetracyclines in treating rosacea has been known for
`more than sixteen years before the priority date asserted by the present application
`
`The use of antibiotic amounts of tetracyclines in treating rosacea has been known
`since as early as the 1984 publication ofWong et al., J. Amer. Acad. Derm. 11:1076-10814
`(hereinafter "Wong") (provided in the February 1, 2012 Information Disdosure Statement).
`The present application asserts a publication date of AprilS, 2001. As mentioned above, the
`prior art does not disclose the method of administering a dose less than the commonly
`prescribed antibiotic dose of a tetracycline compound for treating acne in general, and acne
`rosacea in particular.
`
`The previous assignee ofthe present application, CollaGenex Pharmaceuticals, Inc.,
`launched the first tetracycline drug for rosacea designed to have a dose less than the
`commonly prescribed antibiotic dose of doxycycline in July of 2006. The drug, which is
`called Oracea®, is a 40 mg controlled release dose of doxycycline administered once a day,
`and is covered by the present claims.
`
`It is significant that no one suggested such a drug in the prior art for more than sixteen
`years before applicant' s priority application. It is also significant that no one developed such
`a drug for more than 21 years before CollaGenex launched Oracea®.
`
`4 The use of antibiotic amounts oftetracyclines in treating rosacea has, in fact, been known much longer.
`
`14
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 1S of 18
`
`If it had been obvious to treat rosacea with a dose less than the commonly prescribed
`antibiotic dose of a tetracycline compound, surely someone would have done so in the more
`than 21 years between the publication of Wong and the launehing ofüracea®. At least,
`someone would have suggested doing so in the sixteen years between the December 1984
`publication date of Wong and the AprilS, 2001 filing date ofthe priority date asserted by the
`present application. It is significant, therefore, that no one did.
`
`Bikowski 2003
`
`In addition, a physician, Joseph B. Bikowski, MD, published an article in 2003
`entitled "Subantimicrobial Dose Doxycyline for Acne and Rosacea," SKINmed 6_, 234-24S
`(July-August 2003). The 2003 Bikowski article is attached as ExhibitE.
`
`The article provides important evidence that, as ofthe AprilS, 2001 priority date of
`the present application, the use of a dose less than the commonly prescribed antibiotic dose
`of a tetracycline for acne and rosacea was not known. Applicant, as a matter of full
`disclosure, informs the examiner that Dr. Bikowski was a consultant to the previous
`assignee, CollaGenex Pharmaceuticals, Inc.
`
`The article begins by discussing the pathogenesis of acne and rosacea, and the
`therapies commonly used to treat these conditions. With regard to the mechanism of action
`of antimicrobials in acne, Dr. Bikowski states the following:
`
`The multifactorial nature of acne ideally requires an agent with a
`variety of mechanisms, exerting an effect not only on the bacteria
`but also on the inflammatory host response induced by the
`bacteria.
`
`Seepage 23S, column 2, second paragraph (the page numbers are embedded in the text of
`the publisher's notice at the lower right hand corner (odd-numbers) or left hand corner
`( even numbers) of the pages ).
`
`1S
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 16 of 18
`
`Accordingly, the state ofthe art in 2003 was the same as it was before the April1,
`2001 priority date of the present application. In particular, the state of the art in 2003 was
`that tetracyclines were used for a combination of antibiotic and non-antibiotic effects.
`
`Dr. Bikowski summarizes prior art studies that were designed to measure the
`efficacy of tetracyclines to treat acne in Tables I and II. In all cases, an antibiotic dose was
`used.
`
`Prior art studies involving the use of tetracyclines to treat rosacea are summarized in
`Table III ofthe Bikowski article. For all cases in which the dosewas revealed, an antibiotic
`dose was used.
`
`Dr. Bikowski recognizes the problern ofbacterial resistance that may arise during
`long term treatment with antibiotic compounds. He then speculates as follows:
`
`The exploitation of the anti-inflammatory properties of certain
`antibiotics might be sufficient to elicit a meaningful clinical
`response, and the administration of SDs ( sub-antibacterial doses)
`may provide effective therapy without the risk of soliciting
`alterations in microbial susceptibility ( emphasis added). See page
`236, column 2, the last full paragraph.
`
`Dr. Bikowski further reports that the first double-blind, placebo-controlled, long-
`term clinical trial for the use of a sub-antibiotic dose of doxycycline in acne was conducted
`by Skidmore and reported in an article in 2003. He then reports his own clinical trial for
`sub-antibiotic doses of doxycycline in adult rosacea. He reports that the clinical efficacy
`with sub-antibiotic doxycycline was very similar to results seen with antibiotic doses of
`tetracyclines.
`
`The speculation in Bikowski regarding possible future use ofnon-antibiotic doses of
`tetracyclines, and the reports of first clinical trials in 2003 is significant. The Bikowski
`article constitutes further confirmation that the state of the art even after, and certainly
`before, the present invention was to use tetracyclines for their combination of antibiotic and
`
`16
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 17 of 18
`
`non-antibiotic effects on acne rosacea at antibiotic doses. The first disclosure of the use of
`CMTs or of doses less than commonly prescribed antibiotic doses of tetracyclines to treat
`acne rosacea was in provisional U.S. patent application serial no. 60/281,916 filed AprilS,
`2001, the priority date of which is asserted in the present application.
`
`Commercial success of Oracea® further establishes unobviousness of the present
`claims
`
`Patentability of the present claims is further supported by the significant commercial
`success of Oracea® since its launch in July of 2006.
`
`A graph that illustrates the increasing number of prescriptions of Oracea® sold to
`the public since its launch on July 14, 2006 until December 15, 2007, attached as Exhibit F.
`The graph shows that sales increased from none to nearly 6000 per week over this period.
`
`The successful acceptance of Oracea® by the public is further demonstrated by an
`article in the August, 2006 edition of Dermatology Tim es by a staff correspondent, Rochelle
`Nataloni. The Nataloni article is attached as Exhibit G.
`
`In the article, Ms. Nataloni quoted Dr. James Q. Dei Rosso, Clinical Associate
`Professor in the Department ofDermatology, University ofNevada School ofMedicine (and
`consultant to the previous assignee of the present application, CollaGenex Pharmaceuticals,
`Inc.). Dr. Dei Rosso stated that the treatment ofrosacea " ... has taken a giant step forward
`with the Food and Drug Administration's recent approval ofüracea (emphasis added)." See
`column 1, paragraph 1 ofthe Nataloni article.
`
`Dr. Dei Rosso explained why Oracea® constitutes "a giant step forward," and
`highlighted the unique nature of Oracea, by further stating the following:
`
`Oracea's availability provides a convenient, effective and safe
`oral therapy option that works through anti-inflammatory
`activity and does not produce any antibiotic effects. Oracea is
`the only oral formulation available that can make that claim ....
`
`17
`
`Exh. 1070
`
`

`
`Applicant: Robert A. Ashley
`Serial No.: 13/277,789
`Filed: October 20, 2011
`Page 18 of 18
`
`All of the other oral therapies that are used to treat rosacea ... ,
`such as tetracycline, minocycline and other doxycycline
`formulations exert an antibiotic effect, so it's possible for
`antibiotic resistance to develop while patients are on those
`therapies ...
`
`A statement in a respected dermatological pu