Europaisches
`Patentamt
`European
`Patent Office
`
`Office europeen
`des brevets
`
`Notice of opposition to a European patent
`
`I.
`
`Patent opposed
`
`Patent No.
`
`Application No.
`
`EP1863458
`
`EP06737018.9
`
`Date of mention of the grant in the European Patent Bulletin
`(Art. 97(3), Art. 99(1) EPC)
`
`14 September 2016
`
`Title of the invention
`
`SOLVENT SYSTEM FOR ENHANCING THE
`SOLUBILITY OF PHARMACEUTICAL AGENTS
`
`II.
`
`Proprietor of the patent
`
`first named in the patent specification
`
`Opponent's or representative's reference
`
`Ill. Opponent
`
`Banner Life Sciences, LLC
`
`BD.01.17.EIN
`
`Name
`
`DIECKHOFF Beate
`
`Address:
`
`Dunnwalder Grenzweg 20
`51375 Leverkusen
`Germany
`
`State of residence or of principal place of business
`
`Germany
`
`Multiple opponents (see additional sheet)
`
`Country of nationality
`
`Germany
`D
`
`IV. Authorisation
`
`1.
`
`Representative
`
`Address of place of business
`
`Lohmanns Bernard
`
`Benrather Schlossallee 49-53
`40597 Dusseldorf
`Germany
`
`Telephone/Fax
`
`0211 -86531-0
`
`1 0211 -86531-11
`
`E-mail:
`
`mail@patlaw.de
`
`EPO Form 2300E- BD.01.17.EIN
`
`Page 1 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 1 of 241
`
`

`

`Multiple representatives (see additional sheet)
`
`Authorisation(s)
`
`is/are enclosed
`
`has/have been registered under No.
`
`V. Opposition is filed against
`
`the patent as a whole
`
`claim(s) No(s).
`
`VI. Grounds for opposition:
`
`Opposition is based on the following grounds:
`
`(a) the subject-matter of the European patent opposed is not
`patentable (Art. 100(a) EPC) because:
`
`• it is not new (Art. 52(1); Art. 54 EPC)
`
`• it does not involve an inventive step (Art. 52(1);
`Art. 56 EPC)
`
`• patentability is excluded on other grounds, namely
`articles
`
`(b) the patent opposed does not disclose the invention in a
`manner sufficiently clear and complete for it to be carried
`out by a person skilled in the art (Art. 100(b) EPC; see Art.
`83 EPC).
`
`(c) the subject-matter of the patent opposed extends beyond
`the content of the application/of the earlier application as
`filed (Art. 100(c) EPC, see Art. 123(2) EPC).
`
`D
`
`D
`D
`
`CSJ
`CSJ
`
`D
`
`CSJ
`
`CSJ
`
`VII. Facts (Rule 76(2)(c) EPC)
`
`presented in support of the opposition are submitted herewith
`on an attached document
`
`CSJ
`
`VIII. Other requests:
`
`• Oral proceedings are hereby requested auxiliarily.
`
`EPO Form 2300E- BD.01.17.EIN
`
`Page 2 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 2 of 241
`
`

`

`IX. Evidence presented
`
`D1
`
`Patent document
`
`D10
`
`Non-patent literature(cid:173)
`book
`
`D11
`
`Non-patent literature(cid:173)
`internet
`
`D12
`
`Non-patent literature(cid:173)
`internet
`
`D13
`
`Non-patent literature(cid:173)
`book
`
`D2
`
`Patent document
`
`D3
`
`Patent document
`
`D4
`
`Patent document
`
`D5
`
`Other evidence
`
`D6
`
`Other evidence
`
`US5,360,615 (A) , 01.11.1994
`original file name: 01 - US5360615A.pdf
`attached as: Published-Evidence-1.pdf
`
`Beyer, Walter, "Lehrbuch der organischen Chemie"
`Stutgart: Hirzel, 1988, Ed. 21.
`particular relevance: page 260
`original file name: 010 -Beyer Walter, Lehrbuch der organischen Chemie page
`260.pdf
`attached as: Published-Evidence-7.pdf
`
`Wikipedia , "Excerpt from the U.S. weppage pharmacopeia on PEG (lactic
`acid)"
`, [cited 13.06.2017]
`Available from:
`[http://www. pharmacopeia .cn/v29240/usp29nf24sO_m66430. htm I]
`original file name: 011 -Polyethylene Glycol USP.pdf
`attached as: Published-Evidence-8.pdf
`
`Wikipedia, "Excerpt from the English Wikipedia weppage on citric acid"
`, [cited 13.06.2017]
`Available from:
`[https://en.wikipedia.org/w/index.php?title=Citric_acid&oldid=784172966]
`original file name: 012- excerpt from the Wikipedia weppage on citric acid.pdf
`attached as: Published-Evidence-9.pdf
`
`Beyer, Walter, "Lehrbuch der organischen Chemie"
`Stuttgart: Hirzel, 1988, Ed. 21
`particular relevance: page 283
`original file name: 013 -Beyer Walter, Lehrbuch der organischen Chemie page
`283.pdf
`attached as: Published-Evidence-10.pdf
`
`WO 2016/096580 (A1), 14.09.2006
`original file name: 02 - W02006096580A 1. pdf
`attached as: Published-Evidence-2.pdf
`
`US2001/0007668 (A1), 12.07.2001
`original file name: 03- US2001 007668A 1.pdf
`attached as: Published-Evidence-3.pdf
`
`US5,541 ,210 (A) , 30.07.1996
`original file name: 04- US554121 OA.pdf
`attached as: Published-Evidence-4.pdf
`
`Experiments regarding the Contested Patent filed by the Patentee on
`September 16,
`2011 during the examination procedure
`original file name: 05- Experiments 2011.pdf
`attached as: Other-evidence-1.pdf
`
`Experiments regarding the Contested Patent filed by the Patentee on March
`26,
`2012 with the substantiation of the appeal
`original file name: 06- Experiments 2012.pdf
`attached as: Other-evidence-2.pdf
`
`D?
`
`Other evidence
`
`I Technical data sheet for PEG-600
`
`EPO Form 2300E- B0.01.17.EIN
`
`Page 3 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 3 of 241
`
`

`

`DB
`
`Non-patent literature(cid:173)
`book
`
`D9
`
`Non-patent literature(cid:173)
`internet
`
`original file name: 07- solubility of PEG600.pdf
`attached as: Other-evidence-3.pdf
`
`Beyer, Walter, "Lehrbuch der organischen Chmie"
`Stuttgart: Hirzel, 1988, Ed.21
`particular relevance: page 280
`original file name: 08 - Beyer Walter, Lehrbuch der organischen Chemie.pdf
`attached as: Published-Evidence-5.pdf
`
`Wikipedia , "Excerpt from the German Wikipedia weppage on Milchsaure (lactic
`acid)"
`, [cited 13.06.2017]
`Available from:
`[https://de.wikipedia.org/w/index.php?title=Milchsaure&old id= 165775114]
`original file name: 09- excerpt from the Wikipedia on Milchsaure (lactic acid).pdf
`attached as: Published-Evidence-6.pdf
`
`EPO Form 2300E- B0.01.17.EIN
`
`Page 4 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 4 of 241
`
`

`

`X.
`
`Payment
`
`Mode of payment
`
`I Debit from deposit account
`
`The European Patent Office is hereby authorised, to debit from the deposit account with the EPO any fees and costs indicated in the fees
`section below.
`
`Currency: ~
`
`Deposit account number:
`
`28003075
`
`Account holder:
`
`Bernard Lohmanns
`
`Refunds
`
`Any refunds should be made to EPO deposit account:
`
`28003075
`
`Account holder:
`
`Bernard Lohmanns
`
`Fees
`
`010 Opposition fee
`
`Factor
`applied
`
`Fee
`schedule
`
`Amount to
`be paid
`
`1
`
`785.00
`
`785.00
`
`Total:
`
`EUR
`
`785.00
`
`A
`
`Forms
`
`Details:
`
`A-1
`
`Form for notice of opposition
`
`System file name:
`
`ep-oppo.pdf
`
`B
`
`Attached document files
`
`Original file name:
`
`System file name:
`
`B-1
`
`1. Facts and arguments
`
`OPPOSITION- BD.01.17.EIN.pdf
`
`OPPO.pdf
`
`c
`
`Attached evidence files
`
`Original file name:
`
`System file name:
`
`C-1
`
`1. Patent document
`
`01 - US5360615A.pdf
`
`Published-Evidence-1.pdf
`
`C-2
`
`2. Patent document
`
`02 - W02006096580A 1. pdf
`
`Published-Evidence-2.pdf
`
`C-3
`
`3. Patent document
`
`03- US2001007668A1.pdf
`
`Published-Evidence-3.pdf
`
`C-4
`
`4. Patent document
`
`04- US5541210A.pdf
`
`Published-Evidence-4.pdf
`
`C-5
`
`1. Non-patent literature - book
`
`08 - Beyer Walter, Lehrbuch der
`organischen Chemie.pdf
`
`Published-Evidence-5.pdf
`
`C-6
`
`2. Non-patent literature - book
`
`010- Beyer Walter, Lehrbuch der
`organischen Chemie page 260.pdf
`
`Pu blished-Evidence-7 .pdf
`
`EPO Form 2300E- BD.01.17.EIN
`
`Page 5 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 5 of 241
`
`

`

`C-7
`
`3. Non-patent literature - book
`
`013- Beyer Walter, Lehrbuch der
`organischen Chemie page 283.pdf
`
`Pu blished-Evidence-1 0. pdf
`
`C-8
`
`4. Non-patent literature - internet
`
`09- excerpt from the Wikipedia on
`Milchsaure (lactic acid).pdf
`
`Published-Evidence-6.pdf
`
`C-9
`
`5. Non-patent literature - internet
`
`011 -Polyethylene Glycol USP.pdf
`
`Published-Evidence-S. pdf
`
`C-10
`
`6. Non-patent literature - internet
`
`012- excerpt from the Wikipedia weppage Published-Evidence-9.pdf
`on citric acid. pdf
`
`C-11
`
`1. Other evidence
`
`05- Experiments 2011.pdf
`
`Other-evidence-1.pdf
`
`C-12
`
`2. Other evidence
`
`06- Experiments 2012.pdf
`
`Other -evidence-2. pdf
`
`C-13
`
`3. Other evidence
`
`07- solubility of PEG600.pdf
`
`Other -evidence-3. pdf
`
`Signature of opponent or representative
`
`Place
`
`Date:
`
`Dusseldorf
`
`14 June 2017
`
`Signed by:
`
`Bernard Lohmanns 50454
`
`Capacity:
`
`(Bernard Lohmanns)
`
`EPO Form 2300E- B0.01.17.EIN
`
`Page 6 of 6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 6 of 241
`
`

`

`.··
`
`European Patent Application No. 06737018.9
`BANNER PHARMACAPS, INC.
`PABCX/P38814EP
`
`05
`
`ANNEXA
`
`Experiments to Test the Stability of Compositions of the Invention Against Formation
`of PEG Esters
`
`PRODUCTION OF CAPSULES IN ACCORDANCE WITH THE INVENTION
`
`Active Ingredients
`
`Ingredient
`
`naproxen sodium
`
`Amount per Capsule
`
`220mg
`
`Amount (mg) per Capsule
`
`44.0
`
`17.7
`
`17.7
`
`580.6
`
`Fill Excipients
`
`Ingredient
`
`Lactic Acid
`
`Propylene Glycol
`
`Povidone K-30
`
`Polyethylene Glycol 600
`
`Gelain Shell Excipients
`
`Ingredient
`
`Gelatin
`
`Glycerin
`
`Sorbital Special
`
`Purified Water
`
`ED&C Yellow# 6
`
`FD&C Blue# 1
`
`Using these ingredients capsules were produced using a method as described in the
`
`Examples of European Patent Application No. 06737018.9.
`
`1
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 7 of 241
`
`

`

`...
`
`.··
`
`European Patent Application No. 06737018.9
`BANNER PHARMACAPS, INC.
`PABCX/P38814EP
`
`PACKAGING OF THE CAPSULES
`
`The capsules were either packaged 15 to a bottle or 200 to a bottle or in a bulk carton. The
`
`bottles containing 15 capsules were 45 cc, round, opaque white HDPE bottles with child
`
`resistant caps.
`
`The bottles containing 200 capsules were 400 cc, round, opaque, white, HOPE bottles with
`
`child resistant caps.
`
`STUDY DESIGN
`
`Bottles containing 15 capsules and bottles containing 200 capsules were stored at 25°C and
`a relative humidity of 60% and at 30°C and a relative humidity of 65%. A carton containing
`
`the capsules stored in bulk was stored at 25°C and 60% relative humidity.
`
`The percentage of PEG esters in the capsules, as a percentage of the drug (naproxen
`
`sodium), was determined using HPLC, before storage and after storage for 3 months, 6
`
`months, 9 months and 12 months.
`
`THE RESULTS
`
`TEST WITH BOTTLES CONTAINING 15 CAPSULES
`
`Storage at 25°C/60% Relative Humidity
`
`% PEG-esters
`
`No. Of Months
`
`0
`
`None
`
`None
`
`None
`
`3
`
`0.10%
`
`0.10%
`
`0.10%
`
`6
`
`0.17%
`
`0.17%
`
`0.15%
`
`9
`0.25%
`
`0.25%
`
`0.25%
`
`12
`
`0.32%
`
`0.33%
`
`0.32%
`
`2
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 8 of 241
`
`

`

`..
`
`,•'
`
`European Patent Application No. 06737018.9
`BANNER PHARMACAPS, INC.
`PABCX/P38814EP
`
`Storage at 30°C/65% Relative Humidity
`
`% PEG-esters
`
`0
`
`None
`
`None
`
`None
`
`No. Of Months
`
`3
`
`0.15%
`
`0.15%
`
`0.15%
`
`6
`
`0.28%
`
`0.29%
`
`0.29%
`
`9
`
`0.30%
`
`0.44%
`
`0.44%
`
`12
`
`0.57%
`
`0.58%
`
`0.59%
`
`TEST WITH BOTTLES CONTAINING 200 CAPSULES
`
`Storage at 25°C/60% Relative Humidity
`
`% PEG-esters
`
`0
`
`None
`
`None
`
`None
`
`No. Of Months
`
`3
`
`0.10%
`
`0.11%
`
`0.10%
`
`6
`
`0.17%
`
`0.17%
`
`0.17%
`
`9
`
`0.25%
`
`0.25%
`
`0.24%
`
`12
`
`0.31%
`
`0.32%
`
`0.32%
`
`Storage at 30°C/65% Relative Humidity
`
`%PEG-esters
`
`0
`
`None
`
`None
`
`None
`
`No. Of Months
`
`3
`
`0.16%
`
`0.15%
`
`0.15%
`
`6
`
`0.29%
`
`0.29%
`
`0.28%
`
`9
`
`0.41%
`
`0.45%
`
`0.44%
`
`12
`
`0.57%
`
`0.59%
`
`0.58%
`
`TEST OF BULK PACK CAPSULES
`
`Storage at 25°c/60% Relative Humidity
`
`%PEG-esters
`
`0
`
`None
`
`None
`
`None
`
`No. Of Months
`
`3
`
`0.10%
`
`0.10%
`
`0.09%
`
`6
`
`0.17%
`
`0.16%
`
`0.17%
`
`9
`
`0.25%
`
`0.26%
`
`0.22%
`
`12
`
`0.32%
`
`0.32%
`
`0.32%
`
`3
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 9 of 241
`
`

`

`,.•
`
`...
`
`European Patent Application No. 06737018.9
`BANNER PHARMACAPS, INC.
`PABCXIP38814EP
`
`These results show that initially the capsules of the invention contained no PEG esters and
`that even after storage for up to one year under a variety of storage conditions the capsules
`of the invention contained very low levels of PEG esters.
`In every case, significantly less
`than 1% of the drug had formed PEG esters even after storage for a year. Less than 1%
`PEG ester formation was considered to represent a low level of PEG ester formation which
`did not cause significant loss of activity and therefore compositions with less than 1% PEG
`ester were considered to be stable. All of the capsules tested passed this test.
`
`EVALUATION OF PEG ESTER RESULTS
`
`In addition, the
`The percent PEG esters was plotted versus time (see graph on page 5).
`95% confidence bounds were added to the plot. Both the fitted least-squares line and the
`95% upper confidence bound were extrapolated through 36 months to examine product
`expiration. According to the extrapolated data points for the upper 95% confidence bound,
`the percent PEG esters at 24 months should be 0.65 and according to the fitted least(cid:173)
`squares line, the percent PEG esters should be 0.63. This means that even after three years
`the predicted values from both the upper 95% confidence and the least-squares line did not
`exceed the upper acceptable specification limit of not more than 1.0% PEG esters. In other
`words, compositions of the invention are not predicted to lose activity through PEG ester
`formation after 3 years and to therefore have a shelf life of at least three years.
`
`4
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 10 of 241
`
`

`

`...
`
`Naproxen Sodium 220 mg SGC 25°C/60%) RB
`(%PEG esters vs. Time)
`
`1~---------------------------------.
`
`._
`If)
`......
`Q)
`If) w
`(9
`w
`Q_
`:::R
`
`0
`
`0.75-
`
`0.5-
`
`0.25-
`
`5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 11 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`06
`
`ANNEX TO GROUNDS OF APPEAL
`REPORT OF COMPARATIVE STUDIES CONDUCTED TO COMPARE THE
`PROPERTIES OF COMPOSITIONS OBTAINED IN ACCORDANCE WITH THE
`INVENTION AND THE COMPOSITIONS DESCRIBED IN US 5,360,615
`
`1.0
`
`INTRODUCTION
`
`European patent application no. 06737018.9
`
`is directed to a method of preparing a
`
`pharmaceutical composition.
`
`This method comprises mixing (i) naproxen sodium, (ii)
`
`polyethylene glycol, (iii) hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
`
`fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, acetic acid, proprionic acid, pyruvic
`
`acid, butanoic acid, or lactic acid. Component (iii) is used in an amount of from 0.2 to 1.0 mole
`
`equivalents per mole of naproxen sodium.
`
`An advantage of the present invention is that it provides a reduction in the production of
`
`undesired degradation products such as polyethylene glycol (PEG) esters compared with the
`
`prior art.
`
`The applicant company conducted experiments to demonstrate that preparing a pharmaceutical
`
`composition in accordance with the present invention results in reduced formation of polyethylene
`
`glycol (PEG) esters compared to producing a composition in accordance with the teaching of 01.
`
`Accordingly, the study was designed based on the information provided in D1 and the teaching of
`
`European patent application no. 06737018.9. The compositions tested are summarized in Tables
`
`1, 2 and 3 below.
`
`Page 1 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 12 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`Table 1: Study of compositions prepared in accordance with the present invention
`
`Naproxen
`
`Sodium
`
`Naproxen
`
`Sodium
`
`Naproxen
`Sodium
`
`285mg
`
`220mg
`
`285mg
`
`220mg
`
`285mg
`
`220mg
`
`HCI
`
`HCI
`
`Lactic acid
`
`Lactic acid
`
`Citric acid
`
`Citric acid
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`
`0.6
`
`0.6
`
`0.6
`
`0.6
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`285 mg of Naproxen Sodium is equivalent to 260 mg of the free acid.
`220 mg of Naproxen Sodium is equivalent to 200 mg of the free acid.
`
`Table 2: Study based on the teaching of 01
`Naproxe~~~ :.1\J.~P~~~ eLB.~s~4~~ ti.Approxir.n.~~~411l9-l~_;e;9t.J.LV~IenhJ~velft
`·. · ·~ s~:~,{>;~ .. -~--.·-... _.·_ 1 -... ~-:.~~.:-~ _ _ < · <::·_·-
`._~·· -.:·,
`--
`-· __ ;__
`.. "'· ~~;·, ;. <dt .-.
`-- r.1·
`Form
`-..
`amount__,,.,,,.,~,~·~fi-·.·~it-•~·""z~·~ ·····-
`·;!·~~¥(amount of base)·•"'"''t•r
`-
`
`-:t :,
`
`-
`
`_;~
`
`- •• ,
`
`•
`
`,
`
`_,_ -___ .
`
`• _
`
`Naproxen free 260 mg
`
`acid
`
`200 mg
`
`KOH
`
`KOH
`
`0.2
`
`0.2
`
`0.6
`
`0.6
`
`1.0
`
`1.0
`
`All the experiments were performed using PEG 600. This is a representative example of a PEG
`that can be used in the present invention and was used in some of the Examples of the
`
`application as filed and was also used in Example IV of 01.
`
`Table 3: Study based of compositions containing water
`
`1 : Approximate mole equivalent.
`Naproxen_ .Napro~en. · .. Acid/Ba~e ,water;::
`~~1 .·A:in6J·nt~~ .. ~~~~.- . ~ ·;.·_. "'·""~4~~'J:"·~:~ :·;~leVel ~~-~··•; .·
`-~··
`Form
`.. , .... ,,,. "W'~<k~-~~~ ~~-Ul!.itr--~:<; ·-;;;.~ .• -., ~ :,/:.l,.,.,(amountof,•acid/base).
`···
`·' .• ~ "' • .. ..
`., .. :· ,.,.. ·:.
`- . . .. ' . -" . -... -. . ·*''"""''it'. ''ll:' . ~-.·'
`-
`.
`·.
`_,
`,.,
`~
`Naproxen
`285 mg
`Lactic acid
`8.5%
`0.2
`0.6
`1.0
`
`Sodium
`
`220 mg
`
`Lactic acid
`
`8.5%
`
`0.2
`
`0.6
`
`1.0
`
`Naproxen
`
`free acid
`
`1.0
`0.6
`0.2
`8.5%
`KOH
`260 mg
`~-------+--------~--------~--------+--------+------~
`200 mg
`KOH
`8.5%
`0.2
`0.6
`1.0
`
`Page 2 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 13 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`2.0 MATERIALS
`
`Material
`
`Lot#
`
`6N Hydrochloric Acid
`
`E05P01
`
`PEG-600
`
`Lactic Acid
`
`Citric Acid
`
`100009129
`
`20010740
`
`08-0091
`
`Supplier
`
`J.T. Baker
`
`Banner
`
`Banner
`
`Banner
`
`Potassium Hydroxide
`
`E17K52
`
`J.T. Baker
`
`Naproxen Sodium
`
`S060103
`
`RoChemicallnternational
`
`Naproxen
`
`081M1091V
`
`Sigma-Aldrich
`
`3.0
`
`PROCEDURE
`
`Naproxen sodium or free acid was added to PEG 600 followed by addition of molar equivalent of
`the appropriate acid or based in accordance with the method of the present invention and the
`
`teaching of 01, respectively.
`
`The compositions produced in this manner were subjected to an accelerated stability study.
`
`In
`
`this study the compositions were heated to 60°C for 1 week and analyzed for the amount of
`PEG esters initially and at the end of the accelerated stability study.
`
`The following formulations were prepared:
`
`• Two series of formulations identical to that described in 01 and in the present
`
`application.
`
`• Two series of modified formulations prepared using:
`(1) 220 mg Naproxen Sodium and PEG 600, PG and Povidone were replaced with PEG
`
`600. Three mole ratios of acid or base such as 0.2, 0.6 and 1 were used as
`
`illustrative of the range specified in the claims of the present application.
`
`Page 3 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 14 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`(2) Formulations based on the teaching of 01 comprising Naproxen free acid in an
`
`amount equivalent to the molar amount used in the formulations representative of the
`
`invention, with the same amount of PEG 600 and with KOH.
`
`Samples were analyzed by HPLC:
`
`Agilent 1100 Series HPLC System
`
`Column: DeactiSil ODS-3 5u 100A, 25cm X 4.6mm (ES Industries)
`
`Column Oven Temperature: ambient
`
`Flow Rate: 1.5 mUmin
`
`Injection Volume: 25 uL
`
`UV Detector at 272 nm
`
`Run Time: 60 minutes
`
`Mobile Phase A:
`
`Phosphate Buffer:Acetonitrile (3:2 ratio)
`
`Mobile Phase B:
`
`Phosphate Buffer:Acetonitrile (1 :3 ratio)
`
`Limit of quantitation was approximated to be 0.00011 mg/mL
`
`Page 4 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 15 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`Banner's Formulations
`
`Sample#
`
`Name
`
`Naproxen Na (g)
`
`6N HCI (ml)
`
`PEG-600 (g)
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`NS 285-0.2 HCI
`
`NS 285-0.6 HCI
`
`NS 285-1.0 HCI
`
`NS 220-0.2 HCI
`
`NS 220-0.6 HCI
`
`NS 220-1.0 HCI
`
`NS 285-0.2 lactic
`
`NS 285-0.6 Lactic
`
`NS 285-1.0 Lactic
`
`10
`
`NS 220-0.2 Lactic
`
`NS 220-0.6 Lactic
`
`7.128
`
`7.120
`
`7.152
`
`5.512
`
`5.521
`
`5.548
`
`0.95
`
`2.80
`
`4.70
`
`0.70
`
`2.15
`
`3.60
`
`16.950
`
`15.024
`
`13.514
`
`18.790
`
`17.413
`
`15.891
`
`Naproxen Na (g)
`
`Lactic Acid (g)
`
`Dl H20 (g)
`
`PEG-600 (g)
`
`7.133
`
`7.150
`
`7.132
`
`5.559
`
`5.518
`
`0.513
`
`1.528
`
`2.544
`
`0.388
`
`0.434
`
`1.295
`
`2.167
`
`16.947
`
`15.053
`
`13.188
`
`0.460
`
`18.789
`
`11
`
`12
`
`13
`
`14
`
`15
`
`NS 220-1.0 Lactic
`
`5.523
`
`1.186
`
`1.972
`
`1.030
`
`1.660
`
`17.339
`
`15.899
`
`Naproxen Na (g)
`
`Citric Acid (g)
`
`Dl H20 (g)
`
`PEG-600 (g)
`
`NS 285-0.2 Citric
`
`NS 285-1.0 Citric
`
`NS 220-0.2 Citric
`
`7.129
`
`7.128
`
`5.012
`
`1.020
`
`5.436
`
`0.865
`
`0.439
`
`2.519
`
`0.364
`
`16.364
`
`10.350
`
`18.355
`
`Yu's Formulations
`
`Naproxen API
`
`Naproxen (g)
`
`50% KOH (9)
`
`PEG-GOO (g)
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`Yu 260-0.2 KOH
`Yu 260-0.6 KOH
`
`Yu 260-1.0 KOH
`
`Yu 200-0.2 KOH
`
`Yu 200-0.6 KOH
`
`Yu 200-1.0 KOH
`
`6.499
`
`6.497
`
`6.510
`
`5.027
`
`5.100
`
`5.134
`
`0.330
`
`0.957
`
`1.594
`
`0.286
`0.757
`
`1.230
`
`17.892
`
`16.681
`
`15.357
`
`19.555
`
`18.580
`
`17.540
`
`Page 5 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 16 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`In the tables above, "Banner's formulations" refers to formulations prepared using the method of
`
`the present invention and "Yu's formulations" refers to formulations that are representative of the
`
`teaching of 01.
`
`4.0 RESULTS
`
`The results are summarized in the Table below.
`
`Banner's
`Formulations
`
`Room
`Temperature
`
`Stress at
`SOC for 7-
`Days
`
`Physical
`Observations of
`Formulations
`
`Sam~le#
`
`Name
`
`Peaks RT
`
`%Area
`
`Peaks RT
`
`%Area
`
`Room Tern~
`
`NS 285-0.2
`HCI
`
`NS 285-0.6
`HCI
`
`NS 285-1.0
`HCI
`
`NS 220-0.2
`HCI
`
`NS 220-0.6
`HCI
`
`NS 220-1.0
`HCI
`
`NS 285-0.2
`Lactic
`
`NS 285-0.6
`Lactic
`
`NS 285-1.0
`Lactic
`
`*10.78
`**14.347
`
`0.0084%
`99.9916%
`
`14.36
`
`100.0000%
`
`10.787
`14.34
`
`0.0101%
`99.9899%
`
`10.78
`14.38
`
`0.0030%
`99.9970%
`
`10.753
`14.36
`
`0.0076%
`99.9924%
`
`10.8
`14.4
`
`0.0069%
`99.9931%
`
`10.773
`14.347
`
`0.0076%
`99.9924%
`
`14.4
`
`100.0000%
`
`14.36
`
`100.0000%
`
`14.427
`
`100.0000%
`
`10.773
`14.36
`
`0.0082%
`99.9918%
`
`10.793
`14.413
`
`0.0048%
`99.9952%
`
`10.78
`14.293
`
`0.0075%
`99.9925%
`
`14.36
`
`100.0000%
`
`10.773
`14.287
`
`0.0072%
`99.9928%
`
`14.38
`
`100.0000%
`
`10.767
`14.327
`
`0.0073%
`99.9927%
`
`14.413
`
`100.0000%
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Stress at
`soc 7-Daxs
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Phase Separate,
`precipitate
`
`Clear Solution,
`crystallize at bottom
`
`Clear
`Solution
`
`Phase Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Page 6 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 17 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`NS 220-0.2
`Lactic
`
`NS220-0.6
`Lactic
`
`NS220-1.0
`Lactic
`
`NS285-0.2
`Citric
`
`NS285-1.0
`Citric
`
`NS220-0.2
`Citric
`
`10.767
`14.327
`
`0.0069%
`99.9931%
`
`14.42
`
`100.0000%
`
`10.773
`14.347
`
`0.0067%
`99.9933%
`
`14.407
`
`100.0000%
`
`10.773
`14.367
`
`0.0064%
`99.9936%
`
`14.393
`
`100.0000%
`
`10.747
`14.327
`
`0.0087%
`99.9913%
`
`10.76
`14.38
`
`0.0038%
`99.9962%
`
`10.78
`14.32
`
`0.0021%
`30.4552%
`
`10.78
`14.373
`
`0.0107%
`99.9893%
`
`10.787
`14.353
`
`0.0061%
`99.9939%
`
`14.393
`
`100.0000%
`
`Phase Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`Clear solution
`
`Clear
`solution
`
`White semi-solid
`crystallized
`
`White semi-solid
`crystallized
`
`Phase
`Separate,
`precipitate
`
`Phase
`Separate,
`precipitate
`
`White semi-solid
`paste
`
`White semi-
`solid paste
`
`Opaque solution fill,
`viscuous
`
`Phase
`Separate,
`precipitate
`
`Yu's
`Formulations
`
`Room
`Temperature
`
`Stress at
`SOC for?-
`Days
`
`Physical
`Observations of
`Formulations
`
`%Area
`
`%Area
`
`Peaks RT
`
`'10.773
`.. 14.333
`
`Peaks RT
`
`0.0178%
`99.8580%
`
`10.793
`14.387
`
`0.0132%
`99.8658%
`
`RoomTem~
`Phase Separate,
`preci pilate
`
`Stress at
`soc 7-Da~s
`Clear
`solution
`
`10.767
`14.367
`
`0.0154%
`99.8745%
`
`10.807
`14.387
`
`0.0133%
`99.8689%
`
`Clear solution
`
`10.793
`14.36
`
`0.0160%
`99.8751%
`
`10.813
`14.373
`
`0.0140%
`99.8647%
`
`Clear solution
`
`10.793
`14.393
`
`0.0144%
`99.8879%
`
`10.8
`14.413
`
`0.0093%
`99.8861%
`
`Clear solution
`
`10.787
`14.387
`
`0.0146%
`99.8797%
`
`10.793
`14.4
`
`0.0128%
`99.8784%
`
`Clear solution
`
`Clear
`solution
`
`Clear
`solution
`
`Clear
`solution
`
`Clear
`solution
`
`Clear
`solution
`
`Sam~le#
`
`16
`
`17
`
`18
`
`19
`
`20
`
`Name
`Yu 260-0.2
`KOH
`
`Yu 260-0.6
`KOH
`
`Yu260-1.0
`KOH
`
`Yu 200-0.2
`KOH
`
`Yu 200-0.6
`KOH
`
`Yu200-1.0
`KOH
`
`21
`
`10.787
`14.38
`* PEG ester peak retention time.
`
`0.0148%
`99.8835%
`
`10.807
`14.387
`
`0.0135%
`99.8750%
`
`Clear solution
`
`** Naproxen peak retention time.
`
`Page 7 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 18 of 241
`
`

`

`European Patent Application No.06737018.9
`Banner Pharmacaps, Inc
`PC Ref: PABCX/P38814EP
`
`In general, the amount of PEG ester in the formulations prepared in accordance with the
`teaching of 01 when subjected to stressed conditions varied from 0.0093 to 0.014. The
`
`compositions prepared by the method of the present invention exhibited lower levels of PEG
`esters at room temperature and after the stress study.
`
`5.0 CONCLUSION
`
`The results of these experiments show that formulations prepared in accordance with the
`teaching of the present invention surprisingly contain lower amounts of PEG esters that
`formulations prepared following the teaching of 01.
`
`Page 8 of 8
`
`March 2012
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 19 of 241
`
`

`

`Technical Data Sheet
`
`CARBOWAX™ Polyethylene Glycol (PEG) 600
`
`Product
`Description
`
`CAS # 25322-68-3
`CHEMICAL FAMILY- Oxyalkylene Polymer
`CFTA NOMENCLATURE- PEG-12
`
`Typical Physical Properties- CARBOWAX™ PEG 6000 1 0
`
`07
`
`Range of Avg. Molecular Weight
`Range of Average Hydroxyl Number, mg
`KOH/
`Density, g/cm 3 @ 20oc
`Melting or Freezing Range, C
`Solubility in Water at 20°C, % by wt
`Viscosity at 1 00°C, eSt
`Average Number of Repeating Oxyethylene
`Units
`Avg. Liguid Specific Heat, cal/grc
`Heat of Fusion, Cal/g
`pH at 25°C, 5% Agueous Solution
`Flash Point, Pensky Martens Closed Cup, C
`Flash Point, Cleveland Open Cup, oc
`Physical Form
`Weight per gallon, lbs/gal @ 20oc
`1. Typical properties, not to be construed as specifications
`
`570-630
`178- 197
`
`1.1258
`15-25
`Complete
`10.8
`13.2
`
`0.51
`35
`4.5- 7.5
`238
`274
`Liguid
`9.39
`
`Typical Known Applications for
`Polyethylene Glycols*
`
`•
`Adhesives
`•
`Ceramic Glaze
`• Chemical Intermediates
`•
`Food Packaging
`•
`Inks
`•
`Lubricants
`• Mold Release Agent
`• Plasticizer
`• Wood Treatment
`
`*Refer to the CARBOWAXTM Polyethylene Glycols and Methoxypolyethylene Glycols brochure (Form No. 118-01789-1011) for more specific
`application information
`
`FDA Status
`
`Product
`Stewardship
`
`CARBOWAX™ Polyethylene Glycols are produced to meet the requirements for use under Food
`Additive Regulations for indirect use as components of articles intended for use in contact with food. It
`is the responsibility of the user of CARBOWAX™ PEGs and MPEGs to read and understand all current
`applicable FDA and EPA regulations, as well as any other applicable regulations.
`
`Dow encourages its customers and potential users to review their applications from the standpoint of
`human health and environmental aspects. To help ensure that Dow products are not used in ways for
`which they are not intended or tested, Dow personnel will assist customers in dealing with
`environmental and product safety considerations. Dow literature, including material Safety Data Sheets,
`should be consulted prior to the use.
`
`®TM Trademark of The Dow Chemical Company ("Dow") or an affiliated company of Dow
`
`Form No. 118-01800-1211
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 20 of 241
`
`

`

`Technical Data Sheet
`
`Kinematic Viscosity of A ueous Solutions of CARBOWAX™ Polyethylene Glycol 600
`
`For further information, call ...
`In the United States and Canada: 1-800-447-4369 • FAX: 1-989-832-1465
`In Europe: +800 3 694 6367 • FAX: +3111567 4704
`In the Asia Pacific: +800 7776 7776 • FAX: +800 7779 7779
`In Latin America: +5511 5188 9000 • FAX: +5511 5184 8790
`www.carbowax.com
`NOTICE: No freedom from any patent owned by Seller or others is to be inferred. Because use conditions and applicable laws may
`differ from one location to another and may change with time, Customer is responsible for determining whether products and the
`information in this document are appropriate for Customer's use and for ensuring that Customer's workplace and disposal practices
`are in compliance with applicable laws and other governmental enactments. Seller assumes no obligation or liability for the
`information in this document. NO WARRANTIES ARE GIVEN; ALL IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS
`FOR A PARTICULAR PURPOSE ARE EXPRESSLY EXCLUDED.
`Published December 2011
`
`®TM Trademark of The Dow Chemical Company ("Dow") or an affiliated company of Dow
`
`Form No. 118-01800-1211
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007b, Pg. 21 of 241
`
`

`

`280
`
`2.29 Substitutionsprod ukte aliphatischer Monocarbonsauren
`
`ID81
`
`nichl mit der Estergruppe. Bei der Hydrolyse des Addukts entstehen zunachst P-Hydro(cid:173)
`xycarbonsaureester, die jedoch Ieicht unter Wasseraustritt in die a,{l-ungesattigten Car(cid:173)
`bonsa urccster iibergehen, z. B.
`Br-CH2 - COOCzHs + Zn
`
`BrZnCH2 -COOC 2H5
`/OZnBr
`R-c,
`~· CHz- COOCzHs
`
`R-C=O + BrZnCHz-COOCzHs
`~·
`-ZnBr(OH) R -?- CHz-COOCzHs
`
`+HzO
`
`OH
`I
`
`R'
`/1-Hydroxycarbonsaureester
`
`-H<O
`
`R-C=CH -COOCzHs
`I,
`R
`
`Aldehyde (R'=H) reagieren im allgemeinen Ieichter als Ketone. Die Reaktion wird
`meist durch geringe Zusatze von Iod katalysiert.
`
`Diese mctallorganische Varianle der Aldoladdition kann aufbreiter Basis zu Synthesen verwendet
`werden. Als Carbonylkomponente kommen aliphatische und aromatische Aldehyde sowie alipha(cid:173)
`tische. cyclischc oder aromatische Ketone in Frage (vgl. auch /vanoff-Reaktion), als ,Methylen(cid:173)
`komponente'· unverzweigte und verzweigte aliphatische a. p oder y-Bromcarbonsaureester.
`
`2.29.4.3 y- und .5-Hydroxysauren erhalt man durch alka/ische Hydrolyse der y- bzw.
`6--Halogencarbonsiiuren. Sie konncn jedoch nur in Form ihrer Alkalisalze isolicrt wer(cid:173)
`den, da sie beim Ansauem sofort unter Wasseraustritt in y- bzw. c5-Lactone i.ibergchen,
`z. B.
`
`9'0
`H3C-CH-CH 2-CH 2-C
`'-oH
`I
`Cl
`)~Chlor-valeriansaure
`4-Chlor-va/eriansaure
`
`+KOH
`-KCI
`
`Hzy-yHz
`H3C-CH c=o
`I
`I
`OH OH
`y-Hydroxy-valeriansaure
`
`-HzO
`
`H 2C-CH 2
`'I
`\
`HJC-CH
`C-O
`.......... 0/
`
`y-Valerolacton
`
`Eigenschaften. Die Hydroxysauren sind in Wasser Ieichter, in Ether schwerer loslich als
`die zugehorigen Carbonsaurcn. In Analogie zum Halogen in den Halogencarbonsauren
`erhiiht besonders die a-standige Hydroxylgruppe - wenn auch in geringerem Mal3 -
`dte Acidizdt der Hydroxysauren (-1-Ejfekt). Thr chemisches Verhalten ist durch das
`gleichzeitige Auftreten der alkoholischen Hydroxyl- und der Carboxylgruppe charak(cid:173)
`terisicrt. Sie geben so mit die fiir beide Funktionen spezifischen Umsetzungen.
`Beim l">rhitzen spa! ten die Hydroxysauren Wasser ab und bilden je nach der Stcllung
`der OH-Gruppe nachstehende Verbindungen:
`Aus CJ.-Hydroxysiiuren entstehen unter intennolekularer Wasserabspaltung ringfiirmige
`Lactide, z. B.
`
`H3C-CHOH
`
`I
`
`+
`
`COOH
`Milchsaure
`
`HOOC
`
`I
`HOHC -CH3
`
`-2 HzO
`
`0
`H3C
`'c,...,t'co
`w ..
`z
`6
`1
`1
`orS
`3c-CH3
`........._5__..
`'H
`3,6-Dimethyl-1 ,4-dioxan-2,5-dion
`
`Der Name Lactide ist von der Milchsaure (Acidum lacticum) abgeleitct, an der diese Reaktion zu-
`,a.r-o,;:t h.,.,..)......,,...ht.,t ,,.., .. .....jn
`
`Lactone
`
`j]-Hydroxysiiuren spalten intramolekular Wasser ab unter Bildung a:,{l-ungesall
`Carbonsii.uren, z. B.
`
`CH 2-CHz- COOH
`I
`OH
`P-Hydroxypropionsaure
`
`- HzO
`
`H2C=CH- COOH
`
`Acrylsaure
`
`zuweilen schon bei Raumtemperatur- unter i
`y- bzw. c5-Hydroxysiiuren gehen
`molekularer Wasserabspaltung in y- bzw. i'!-Lacwnc iiber, z. B.
`Hz
`/c,
`CHz
`H2C
`I
`I
`HzC
`CO
`I
`I
`OH
`OH
`8-Hydroxy-
`valeriansaure
`
`-Hfl
`
`Hz c
`H c/ 'cH
`21
`I 2
`_co
`H2c
`'o'
`8-Valerolacton
`
`H2C-CH 2
`HzC-CH 2
`I
`I
`- I \
`HzC CO
`-HzO HzC
`CO
`'o/
`I
`I
`HO OH
`y-Hydroxy(cid:173)
`buttersaure
`
`y-Butyrolacton
`
`Analog