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`PHARMACEUTICALS
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`AMNEAL 1021
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`
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`1
`
`

`

`LABORATORY NOTEBOOK
`
`LABORATORY NOTEBOOK GUIDELINESt
`
`l't9TEBOOK_~_Q~___2_,D"---L'16"-=2-_______________________________ ~---------
`
`CONTINUED FROM NOTEBOOK NO.
`
`CONTINUED TO NOTEBOOK NO.
`
`ASSIGNED TO:
`
`SIGNATURE
`
`DATE
`
`'
`
`PATE ISfi!lm _____ __ll[__,__!---'Lt_,__/-'=2,o'-'-'l3--.· - - - - - -=Bv _ __(WyA ___________________________________________ _
`
`---------------~~~~~~
`
`PHONE
`
`Q..QMl'fl_lll_y _____ _
`
`DEPARTMENT
`
`AD_t;JRESS
`
`EMAIL
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`~~~~------------------------- --------------------·
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`QJTY ----------------------------------- -~-
`
`STATE
`
`Z~I~P ______________ _
`
`NOTES:
`
`____ NWM_Il!;B_OF PAGEs.ELL.Lf:.Qli'L ____________________________________ _
`
`www.vwr.com
`
`VWRCl!7
`INTERNATIONAl
`
`LABORATORY NOTEBOOK INTRODUCTION
`Using a Laboratory Notebook to record ideas, inventions,
`experimentation records, observations and all work details is a
`vital
`part
`of any laboratory process. Careful attention to how you keep
`your Laboratory Notebook can have a positive impact on the
`patent outcome of a pending discovery or invention.
`Following are some overall recommendations to help you keep
`more efficient and accurate Laboratory Notebook entries.
`Remember, however, that these are simply a suggested set of
`guidelines. Only your attorney can supply the exact guidelines
`she would like you to follow to satisfy specific legal require(cid:173)
`ments. That is why we recommend that you consult your legal
`counsel.
`
`RECORDING DATA
`Your Laboratory Notebook is a vital record of your work whether
`it is for patent purposes, legal records or documenting drug
`research under FDA guidelines. The Laboratory Notebook can
`help you prove:
`a. Exact details and dates of conception
`b. Details and dates of reduction to practice
`c. Diligence in reducing your invention to practice
`d. Details regarding the structure and operation of your
`invention
`e. Experimentation observations and results
`f. A chronological record of your work
`g. Other work details
`
`Follow a few simple rules of thumb
`1. Always record entries legibly, neatly and in permanent ink.
`2. Immediately enter into your notebook and date all original
`concepts, data and observations, using separate headings
`to differentiate each.
`3. Record all concepts, results, references and other infor(cid:173)
`mation in a systematic and orderly manner. (Language,
`charts and numbering systems should be maintained con(cid:173)
`sistently throughout.)
`4. It is acceptable to make your entries brief. Always, howev(cid:173)
`er, include enough details for someone else to successful(cid:173)
`ly duplicate the work you have recorded.
`5. Label all figures and calculations.
`6. Never, under any circumstances, remove pages from your
`notebook.
`
`Remember to treat your Laboratory Notebook as a legal
`document: It records the chronological history of your activi(cid:173)
`ties. The following guidelines should help you maintain the con(cid:173)
`sistent and accurate entries needed for future legal purposes.
`1. Start entries at the top of the first page, and always make
`successive, dated entries, working your way to the bottom
`of the last page.
`2. After completing a page, sign it before continuing to the
`next page.
`3. Make sure that you record the date of each entry clearly
`and unambiguously.
`4. Never let anyone other than yourself write in your
`Notebook (excluding witness signatures, discussed later).
`
`5. Never leave blank spaces, and never erase or remove
`material you have added. Simply draw lines through any
`blank spaces at the same time you are making your
`entries.
`6. Do not erase errors. Just draw a single line through any
`·erroneous entry, then add your initials. Enter the correct
`entry nearby.
`7. You can supplement your entries with supporting material
`(e.g., test-result printouts and other documentation). But
`you must permanently affix the material onto a page in its
`proper chronological location.
`8. Never rely solely on any supplemental attachment. Always
`include your own entry describing the attachment and add
`any conclusions that you might draw from its substance.
`9. Occasionally, secondary sources might be too large or
`inappropriate to attach directly to your notebook. In this
`case, you can add all secondary sources to an ancillary
`record maintained precisely for this purpose. However,
`always remember to write a description of these second(cid:173)
`ary sources, clearly and unambiguously, in your notebook.
`
`DOCUMENTING PATENT ACTIVITIES
`A primary purpose of a Laboratory Notebook is the support of
`documenting work that may be patentable. To support patent
`activities, it is necessary to provide clear, concise, chronologi(cid:173)
`cal entries with specific dates. To rely on these dates, you must
`have at least one non-inventor corroborate that the events
`actually happened and that he or she understood your inven(cid:173)
`tion by signing and dating the "Disclosed to and Understood by''
`signature blocks.
`Your Laboratory Notebook should help you document and
`prove:
`1. Conception Date-The date that you knew your invention
`would solve the problem.
`2. Date of reduction to practice-The moment that you made
`a working embodiment of your invention.
`3. Diligence in reducing your invention to practice-Diligence
`refers to your intent and conscious effort to make a work(cid:173)
`ing embodiment. You are not required to rush, or even to
`take the most efficient development strategy. But your
`Notebook must include details relating to your diligent
`activities. These are dates and facts that show what activ(cid:173)
`ities you have conducted to reduce the invention to prac(cid:173)
`tice, and when such activities were conducted. Since you
`may still be diligent despite periods of not working on
`reducing your invention to practice, always remember to
`provide reasonable excuses for these periods of inactivity
`by supplying facts relating to why there was no activity
`during the period in question. (e.g., unavailability of test
`conditions or equipment).
`4. How to make and use your invention-provide documen(cid:173)
`tation details sufficient to teach a colleague how to make
`and use your invention.
`5. The best mode of practicing your invention-document the
`best way to practice your invention.
`A non-inventor colleague should corroborate each of these
`events/facts by signing the "Disclosed to and Understood by"
`on the relevant pages.
`
`t VWR provides these sample guidelines "AS IS" without any
`warranty.
`
`[69005-130V02 Sep·2005]
`
`2
`
`

`

`TABLE OF CONTENTS
`
`~
`
`1
`
`3
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`3
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`

`

`TABLE OF CONTENTS
`
`TABLE OF CONTENTS
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`PAGE
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`

`

`TABLE OF CONTENTS
`
`TITLE
`
`'P-
`
`.
`
`•
`
`•
`
`PROJECT
`'
`
`. . :
`
`BOOK
`
`[
`
`[ . •
`
`; I
`
`£'[1_(3!= _____ ---------------------- ----- - -------
`97
`
`DATE
`
`98
`
`102
`
`107
`1---------+··-··---··-···---------------
`108
`
`- - ---------------- . -- --------------------------·--·-·-- --- - -- --
`
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`
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`111
`
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`
`112
`
`115
`
`1-- -- -+--------------------------------- ----------------·. ·-. -·-·- ------.. -· -----· -·-· ---· -· -·---· -·--
`
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`
`45
`
`'
`SIGNATURE
`
`•
`
`DATE
`
`i
`
`PROPRIETARY INFORMATI
`
`5
`
`

`

`November II, 2013
`
`To:
`
`Anita Kumar
`
`From: Dr. Tony Palmieri
`Dr. Vivian Gray
`
`Re:
`
`Endo Pharms., Inc. v. Amneal Pharms., LLC, Case No. I :12-cv-8115 (S.D.N.Y.)
`Formulation and Testing Protocol of Controlled-Release Oxymorphone Tablets
`
`The following memorandum sets fmth a protocol to formulate controlled-release
`oxymorphone hydrochloride as disclosed in WO 01/08661 A2 (Maloney) and to conduct in vitro
`dissolution testing of sample batches under the conditions detailed in U.S. Patent Nos. 8,309,122
`and 8,309,216, which are recited below. As you prepare and test these tablets, please be sure to
`record any variables (e.g., air compression) that you may need to adjust but are not explicitly
`noted below. Retain copies of documents and information generated during the manufacture and
`testing of the sample batch, including but not limited to lab notebooks, batch records, and
`calibration curves.
`
`I. Create Sample Batches of Controlled-Release Tablets Containing Oxymorphonc
`Hydrochloride
`
`Subparts A and B outline the formulas and steps required to formulate and
`manufacture two batches of at least I ,000 controlled-release tablets each.
`
`A. Formula #1
`
`The formula for the first sample batch of controlled-release tablets should include the
`following ingredients by weight:
`
`INGREDIENT
`
`AMOUNT
`
`Oxymorphone hydrochloride
`
`30 mg (20% w/w)
`
`Lactose, NF (Fast Flo)
`
`Amber lite IRP 69M Fine
`Pmticle Size
`
`Methocel KIOOM (Premium)
`CR
`(hydroxypropylmethylcellulose,
`USP)
`
`39.5% w/w
`
`5.0%w/w
`
`30.0%w/w
`
`Cab-0-Sil (M-5)
`
`0.5% w/w
`
`- 1 -
`
`Stearic Acid, NF (Powder)
`
`Theoretical Tablet Weight
`
`5.0%w/w
`
`150 mg
`
`B. Formula #2
`
`The formula for the second sample batch of controlled-release tablets should include the
`following ingredients by weight:
`
`INGREDIENT
`
`AMOUNT
`
`Oxymorphone hydrochloride
`
`30 mg (20% w/w)
`
`Lactose, NF (Fast Flo)
`
`Amberlite lRP 69M Fine
`Particle Size
`
`Methocel K!OOM (Premium)
`CR
`(hydroxypropylmethylcellulose,
`USP)
`
`Cab-0-Sil (M-5)
`
`Stearic Acid, NF (Powder)
`
`Theoretical Tablet Weight
`
`24.5%w/w
`
`5.0%w/w
`
`45.0%w/w
`
`0.5%w/w
`
`5.0%w/w
`
`150 mg
`
`C. Manufacturing Steps
`
`In manufacturing the sample batch of controlled-release tablets, please follow_ these steps
`in order. Please Jet us know immediately if you need to devmte from these steps m any
`manner.
`
`Obtain Amber lite JRP 69M Fine Particle Size. If Fine Particle Size is not
`)
`available, ~ease process the Amberlite by passing it thro~gh a 325 mesh _(U.S._ Standm:d
`mesh size) or by using other conventional methods to ach1eve a mean pa1t1cle s1ze that IS
`about 27 ]lm, or at least less than 44-50 ]lm.
`
`b)
`
`c)
`
`d)
`
`Pass Lactose NF (Fast Flo) through a No. 20 mesh screen for delumping;
`
`Mi II the Lactose;
`
`Pass the Cab-0-Sil (M-5) (a glidant), oxymorphone hydrochloride USP
`and Amberlite IRP-69M fine pa1ticle size through a No. 20 mesh screen
`for delumping and mix with the lactose for I 0 minutes to create a drug
`powder blend;
`
`- 2-
`
`6
`
`

`

`e)
`
`f)
`
`g)
`
`h)
`
`i)
`
`(Methocel Kl OOM
`the hydroxhypropylmethylcellulose USP
`Pass
`(premium) CR) through a No. 20 mesh screen for delumping;
`
`Then add the drug powder blend and mix for 20 minutes;
`
`Pass stearic acid NF (powder) through a No. 40 mesh screen and add to
`the batch;
`
`Then mix the batch for 5 minutes;
`
`Then compress the final blend to form tablets using a conventional tablet
`press and conventional tooling to form tablets of conventional hardness for
`extended-release dosage forms.
`
`II.
`
`Testing of Dissolution Rate of Sample Batches Created in Step 1
`
`The steps below outline in vitro dissolution tests, using six samples from each batch
`created in prut I. For the "USP Paddle Method," see Attachment A at§ 711, Dissolution for
`explanation on the parameters of the USP Paddle Method.
`
`Please perform the following in vitro dissolution testing method: USP Paddle
`in vitro
`Method at 50 rpm in 500 mL media at 37° C. Please perform the
`dissolution test using three different pH levels: 1.2, 4.5, and 6.8.
`
`For each tablet and pH tested, measure and record below the release of
`oxymorphone hydrochloride (in milligrams) at hours: I, 2, 3, 4, 5, 6, 8, 10, and
`12.
`
`Time (Hr)
`
`pH
`
`Oxymorphone Hydrochloride
`released into the solution (mg).
`
`I
`2
`3
`4
`5
`6
`8
`10
`12
`
`Again, please retain copies of documents and information generated during this expert,
`including but not limited to lab notebooks, batch records, and calibration curves.
`
`- 3 -
`
`TITLE To PeA~ ·rrn
`
`PROJECT 0 :X ~yp/;WYV 1-1.0
`
`- 5
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`
`_____ ;..
`
`____ ,
`
`·----!
`
`_____ j
`
`PROPRIETARY INFORMATim
`
`7
`
`

`

`-\JPl6 }L • 6
`BOOK
`PAGE
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`PROJECT Ox
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`PD I& 2... • 8
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`
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`40
`
`45
`
`SIGNATURE
`
`PROPRIETARY INFORMATION
`
`DISCLOSED TO AND UNDERSTOOD BY
`
`PROPRIETARY INFORMATION
`
`9
`
`

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`2.269
`
`2.270
`2.270
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`2.270
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`9547
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`BOOK
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`Page: 1 of 1
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`Project Name: Oxymorphone HCI Tablets ....... +---c--+ -j
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`PROPRIETARY INFORMATION
`
`13
`
`

`

`I v 1!> ~ -
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`BOOK
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`ll'S
`PAGE
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`ru to~- 19
`BOOK
`PAGE
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`TITLE Tv pe.JJ-v'(Y'-\_ aUssoLu;,'on S~ PROJECT ID.x ~ i'V1.(l) yp hsvw...
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`System Suitability Summary Results
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`Name: Ox mor hone HCI
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`10
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