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`
`discloses the claimed compound in at least two salt forms
`and further discloses
`that
`the
`sodium salt of
`the
`compound is sold as Remodulin® which ts an FDA
`approved treatment. Paragraph[0051].
`
`|
`
`Cc.
`
`Invalidity of United States Patent No. 7,999,007
`
`United States Patent No. 7,999,007 is entitled “Buffer solutions having selective
`
`bactericidal activity against gram negative bacteria and methods of using same.” The ’007
`
`patent issued on August 16, 2011 and claims the priority date of September 7, 2007. The central
`
`feature of each of the asserted claims is the combination oftreprostimil and glycine buffer with a
`
`pH of greater than 10.
`
`In November 2004, Remodulin (treprostinil) was approved for intravenous use for the
`
`treatment of pulmonary hypertension. When administered intravenously, Remodulin must be
`
`diluted prior to infection. At the time, the approved diluents were Sterile Water for Injection or
`
`0.9% Sodium Chloride for Injection. Around September 2006, Dr. Robyn Barst, a pulmonary
`
`hypertension specialist, contacted UTC and the CDC to inform them she was observing that
`
`patients receiving intravenous Remodulin were experiencing higher rates of blood stream
`
`infections than patients receiving intravenous administration of another pulmonary hypertension
`
`medication called Flolan®. Unlike Remodulin, which was diluted with water or saline, Flolan®
`
`was diluted with Sterile Diluent for Flolan®. Sterile Diluent for Flolan® is a glycine buffer with
`
`a pH of 10.5.
`
`In response, the CDC conducted an investigation and published its results in
`
`March, 2007, confirming that the incidence of biood stream infections was greater in patients
`
`receiving intravenous Remodulin® than in patients receiving intravenous Fiolan®.
`n
`September 7, 2007, six months after the CDC report was published and approximately a year
`
`On
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`after Dr. Barst first raised the infection issue, UTC filed the application that later matured into
`
`the ‘007 patent.
`
`The asserted claims of the 007 patent generally are directed to methads of(1) selectively
`
`killing gram negative bacteria and inhibiting the growth of gram positive bacteria in a
`
`pharmaceutical preparation comprising supplying an active ingredient with “a buffer comprising
`
`glycine having a pH of greater than 10” (claims 1-10); (11) methods of reducing the “occurrence
`
`of blood stream infections’ in a mammal comprising “administering to a mammal the active
`
`agent with a buffer comprising glycine and having a pH of greater than 10” (claims 11-21); and
`
`(iii) pharmaceutical compositions in a solution “comprising glycine and with glycine and having
`
`a pH greater than 10” (claims 22-26).
`
`i.
`
`Claims 1-5, 7-17 And 19-26 Of The °007 Patent Are Anticipated by EP
`0347243A1 Or Obvious Over EP 0347243Al
`in View Of Sterile
`Diluent for Mlolan And Knowledge Of One Of Ordinary Skill In The
`Art.
`
`The asserted patent claims 1-5, 7-17, and 19-26 of the ’007 patent are invalid, because
`
`they are anticipated by European Patent Application EP 034724341 (EP ’243”) or obvious over
`
`EP °243 in view of Sterile Diluent For Flolan and/or knowledge of one of ordinary skill in the
`
`priorart.
`
`EP °243 issued on December 20, 1989, and is, thus, 102(b) prior art. EP °243 patent
`
`disciosed and claimed medicaments for the treatment of pulmonary hypertension that could be
`
`used subcutaneously or intravenously. EP 243, #22, 25. Example 1 discloses the combination
`
`of treprostinil and a “glycine butfer” with a pH of 10.5. EP °243 further describes the use of
`
`buffer solutions with treprostinil
`
`to treat pulmonary hypertension. EP °243 concludes that
`
`treprostinil used with a glycine buffer solution of greater than pH 10 “was found to reduce
`
`hypoxia-induced increase in pulmonaryarterial pressure and pulmonary vascular resistance in a
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`dose-related manner without appreciably affecting cardiac output or heart rate.” fd. at Jf 32-34.
`
`EP °243 discloses that “sterile” acqueous solutions are preferred and that “[sJuch preparations
`
`may conveniently be prepared by admixing the compound with water or a glycine buffer and
`
`rendering the resulting solution sterile and isotonic with the blood.” /d@ at 925. Therefore, EP
`
`°243 discloses “a pharmaceutical preparation” or “pharmaceutical composition” comprising
`
`“treprostim|” and “a buffer comprising glycine and having a pH of greater than 10.” Having a
`
`low buffer capcity and the intended purpose—killing bacteria and reducing infections—are
`
`inherent properties of a sterile solutions that are sterile and isotonic with the blood. /d
`
`If EP °243 does not anticipate the 007 patent, °607 patent is invalid as obvious over EP
`
`*243 patent in view of the commercial embodiment Sterile Diluent for Flolan®. Ficlan® is a
`
`third party competitive product, containing epoprostenol, which was approved in 1995 for
`
`treating pulmonary hypertension. Flolan® is a powder that must be reconstituted with “Sterile
`
`Diluent for Flolan” (“SDF”). SDFis a solution containing the amino acid glycine and having a
`
`pH greater than 10 that physicians or patients may use to dilute Flolan prior to intravenous
`
`infusion. The use of SDF (or a buffer such as SDF) was described, for exampic,
`
`in 1999
`
`Flolan®label and U.S. Patent No. 4,335,139. SDF was available more than | yearpriorto the
`
`earliest priority date of the '007 patent and is 102(b) priorart to the ’007 patent.
`
`A person of ordinary would have found it obvious to combine Remedulin in combination
`
`with SDF, based on EP °243, SDF and knowledge of one of ordinary skill in the art, with a
`
`(LS. Patent No. 4,335,139 wascited by the Examiner during the prosecution of U.S. Patent No. 8,658,694 and
`appcars on the facc of 2000 Flolan® label.
`The °139 patent discloscs the use of a prostacyclin with “a
`pharmaceutically acceptable buffer having a pH value ofat least 9 and based on an amino acid as the principal
`buffering acid in the buffer.” °139 patent, col. 1, lines 38-45, “Such a solution and all solutions hereinatter referred
`to are, for medicinal purposes,
`to be understood to be sterile solutions.” fa at col. 2, lines 4-6.
`“Glycine” is
`specifically disclosed as an amine acid of the buffer.
`/@ at Example 1. Example 7 specttically discloses a sterile
`diluent for injection of a prostacyclin, which contains glycine and has a pH of 10.5. The 2000 Flolan label
`imcorporated by reference the °139 patent as covering Flolan®and SDF.
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`reasonable expectation of success. ASR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). As
`
`of the priority date of the ’007 patent, Remodulin (treprostinil) was the commercially-available
`
`treprostinil product, and SDF was the only commercially-available glycine buffer with a pH of
`
`10.5, already in use with another pulmonary hypertension medication. And as the district court
`
`in the related case, U/7C v. Sandoz, 12-CV-G1617, 13-CV-316 (D.N.J. 2014), expressly found,
`
`this combination would meet all of the asserted claims of the °907 patent.
`
`(Decision at 73.)
`
`UTC’s expert in the related Sandoz matter, Dr. Michael Miller, admitted at trial that a person of
`
`ordinary skill in the art, seeking to practice the invention disclosed and claimed in EP °243, could
`
`easily have done so by combining Remodulin and Sterile Diluent for Flolan, both of which were
`
`commercially available products as of the priority date for the ’007 patent.
`
`A person of ordinary skill in the art also would have been motivated to use treprostinil
`
`with a high pHbuffer comprising giycine with a reasonabie expectation of success in inhibiting
`
`bacterial growth or reducing the occurrence of blood stream infections. The use of SDF resulted
`
`in a high pH glycine buffer solution that was sterile, antibacterial and anti-infective. Moreover,
`
`it was well-known in the prior art that glycine is an amino acid that has antibacterial properties.
`
`See e.g. Foegeding P.M. et al, “Chemical Food Preservatives,” Ch. 47 at 825 in Disinfection,
`
`Sterilization and Preservation 4" Ed. 1991; Hammeset al., “Mode of Action of Glycine on the
`
`Biosynthesis of Peptidoglycoan,” J. Bacteriology, Vol. 116, No. 2 pp. 1029-1053 (1973);
`
`Strominger et al., “Nucleotide Accumulation Induced in Staphylococcus aureus by Glycine,” J.
`
`Bacteriology, Vol. 89, No. 4 pp. 1124-1127 (1965). Therefore, as of the priority date, it was aiso
`
`known that a solution in an alkali environment (high pH solutions) with givcine will have
`
`bactericidal antiinfective effects. See, e.g., Mendonca, et al, “Destruction of Gram-Negative
`
`Food-Borne Pathogens by High pH Involves Disruption of the Cytoplasmic Membrane,: Applied
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`and Environmental Microbiology, vol. 60, No. 11, p. 4009-4014 (1994).
`
`(Mendoneca”’)
`
`(disclosed during the prosecution of the
`
`°007 patent); Crowther et al.
`
`“Growth of
`
`Microorganisms in Propofol, Thiopental, and a
`
`1:1 Mixture Of Propofol and Thiopental,”
`
`Anesth. Analg., 82: 475-478 (1996) Crowther”) (TEVATRE0004034-7); and Siqueira et al.,
`
`Mechanisms of antimicrobial activity of caicitum hydroxide:
`
`a critical
`
`review,” Intern.
`
`Endodontic J., 32, pp. 361-369, (1999) (“Siqueira) (TEVA_TRE_0004298-306).
`
`Consistent with the fact that glycine and high pH solutions have known antibacterial
`
`properties,
`
`the prior art describes glycine buffer solutions that have high pH used in
`
`pharmaceutical formulations. U.S. Appln. No. 10/137,331; 1999 Flolan Package Insert; EP ’243;
`
`Wade 2005 [0030], 2005 PDR.
`
`Indeed, the prior art specifically describes with treprostinil with
`
`high pH glycine buffer solutions for use in pharmaceutical compositions. EP ’243; Wade 2005.
`
`Moreover, a person of ordinary skill would have been motivated to address possible
`
`complications from bacterial infections when the drug is administered intravenously.
`
`A solution having “a lowbutfer capacity” also would have been knownto a person of
`
`ordinary skill in the art. Claims 1-5, 7-10, 16-17, and 21 also requirethat the glycine buffer used
`
`in the claimed methods have a low buffer capacity. The ’007 patent states that “the buffer
`
`capacity should be low to avoid pH changes in the blood upon infusion.” Col. 2, lines 34-35.
`
`SDF inherently possesses this limitation. Moreover, it would have been obvious to a person of
`
`ordinary skill in the art that it is important to maintain the proper pH of blood to avoid possible
`
`severe complications. See e.g. Petrucci, R. and Harwood, W., Generali Chemistry Principles and
`
`Modern Applications, 6" Ed., 1993, pp. 656-57 (explaining that the normal pH of blood is 7.4
`
`and increased pH of blood can lead to severe vomiting and hyperventilation). Consequently, it
`
`would have been obvious to a person of ordinary skill to formulate the high pH buffer solution
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`with a low buffer capacity, so that it would be safe and avoid any complications based on
`
`changes of blood pH whenthe treprestinil solution is administered. See a/so EP ’243 at 5.
`
`The dependent claims the depend fromclaim 1 are obvious for the same reasons as stated
`
`above. Furthermore, dependent claim 2 requires that the active agent is treprostinil sodium. The
`
`prior art specifically describes the use of glycine buttered solutions with treprostinil. EP °243;
`
`Wade 2005 [0030]. Also, the 2006 Remodulin Package Insert describes the use oftreprostinil as
`
`the active ingredient. Dependent claim 3 requires the buffer to contain sodium hydroxide. SDF
`
`contained sodium hydroxide. Moreover, the 1999 Flolan Package Insert, the 2005 PDR, and
`
`Calbiochem describes sodium hydroxide used in the giycine butter solution. Dependent claims 4
`
`and 5 require the butter solution to have a pH between about 10 to about 12 or 10.2 to 10.8,
`
`respectively. The 1999 Flolan Package Insert and the 2005 PDR, and Calbiochemdescribe the
`
`pHofthe glycine buffer from 10.2 to 10.8, and EP "243 describes such a formulation at Example
`
`1. Dependent claim 7 requires the active agent to be at a concentration between about 0.001
`
`mg/mL to about
`
`| mg/mL, and dependent claim 8 requires treprostinil sodium to be at a
`
`concentration between about 0.004 mg/mL to about 0.13 mg/mL. EP °243 and the 2006
`
`Remodulin Package Insert disclose concentrations that cover this ranges.
`
`EP °243 at 5.
`
`Dependent claims 9 and 10 require that pharmaceutical preparation is injected, for claim 10
`
`injected intravenously, into a mammal in need thereof. EP °243, 1999 Flolan Package Insert, the
`
`2005 PDR,the 2006 Remodulin Package Insert, and Wade 2005 all describe the injection of the
`
`pharmaceutical preparation into mammals for treatment.
`
`The dependent claims the depend from claim 11 are obvious for the same reasons as
`
`stated above. Furthermore, dependent claim 12 requires that a human subject undergoing the
`
`method has pulmonaryarterial hypertension. EP ’243, 1999 Flolan Package Insert, the 2005
`
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`PDR, the 2006 Remodulin Package Insert, and Wade 2005 all describe the use of the active
`
`ingredient to treat pulmonaryarterial hypertension. Also, the dependent claims the depend from
`
`claim 22 are obvious for the sarne reasons as stated above.
`
`Plaintiff has not set forth its contentions concerning secondary considerations in this case.
`
`If Plaintitf relies on any secondary considerations of non-obviousness, Teva reserves the nght to
`
`supplement its contentions.
`
`2.
`
`Claims 1-5, 7-17, And 19-26 Of The °607 Patent Are Not Enabled
`And/Or Lack A Written Description
`
`As explained above, a person of ordinary skill in the art would have found the asserted
`
`claims anticipated or obvious in view of the prior art. A person of ordinary skill would have
`
`been able to take the information in the prior art and apply routine experimentation to arrive at
`
`the methods and compositions of the asserted claims. But if Plaintiff contends that that the
`
`asserted claims are not invalid because a person ofordinary skill would need to practice undue
`
`experimentation from the disclosures in the prior art, then the asserted claims are invalid because
`
`they are not enabled and the patent does not contain a sufficient written description.
`
`The °007 patent generally describes solutions with an active ingredient, glycine, a high
`
`pH, and a low buffer capacity. Further, it gives general and broad ranges for these ingredients
`
`and requirements and specitically does not restrict them to indicate that only a narrow rangefor
`
`those ingredients and requirements will work. For example, it describes glycine concentrations
`
`“of about 30%to about 80%” and an active ingredient concentration of preferably 0.004 mg/mL
`
`to about 6.13 mg/mL.
`
`Hf Plaintiff contends that the prior art is not enabled or a person of
`
`ordinary skill would need to conduct undue experimentation based on the disclosures in the prior
`
`art, then the asserted claims of the 007 patent would lack enablement and fail to meet the written
`
`description requirement because a person of ordinary skill in the art would need to conduct
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`undue experimentation to enable the full scope of the claims, and the patent lacks any written
`
`description as to all of the alleged proper parameters for the claimed methods and compositions.
`
`The following prior art shows all of the limitations of the °007 patent, including the use
`
`of glycine buffers to inhibit bacterial growth or reduce bioodbourne infections, prior to
`
`September 7, 2007, the priority date of the °007 patent:
`
`# EP ?243 (TEVA_TRE_0004270-80)
`
`# US. Patent Publication No. 2005/0165110 July 2005, Wade et al. (Wade 2005”)
`(TEVATRE0004213-218)
`
`® Crowtheret al., “Growth of Microorganisms in Propofol, Thiopental, and a 1:1 Mixture
`Of Propofol and Thiopental,” Anesth. Analg, 82: 475-478 (1996)
`(“Crowther”)
`(TEVATRE_0004034-7)
`
`#
`
`®
`
`Siqueira et al., Mechanisms of antimicrobial activity of calcium hydroxide: acritical
`review,”
`Intern.
`Endodontic
`J,
`32,
`pp.
`361-369,
`(1999)
` (Siqueira)
`(TEVATRE0004298-306)
`
`al, “Chemical Food Preservatives,’ Ch. 47 in Disinfection,
`et
`Foegeding P.M.
`Sterilization and Preservation 4" Ed. 1991. (TEVA_TRE_0004267-9}
`
`® Hammes et al., “Mode of Action of Glycine on the Biosynthesis of Peptidoglycoan,” J.
`Bacteriology, Vol. 116, No. 2 pp. 1029-1053 (1973) (TEVATRE0004042-66)
`
`®
`
`»
`
`#
`
`=
`
`Strominger et al, “Nucleotide Accumulation Induced in Staphylococcus aureus by
`Glycine,” J. Bacteriology, Vol. 89, No. 4 pp. 1124-1127 (1965) (TEVA_TRE_0004038-
`41)
`
`“Buffers: A guide for the preparation and use of buffers in biological systems” by
`Calbiochem (“Calbiochem”) (TEVATRE6003997-4033}
`
`2006 Remodulin Package Insert (TEVA_TRE_0004285-97)
`
`1999 Flolan Package Insert (TEVA_TRE0004281-84)
`
`# The 2005 Physicians’ Desk Reference for Flolan® (epoprostenol sodium for injection)
`(“2005 PDR”) (TEVATRE0003991-6)
`
`®
`
`Petrucci, R. and Harwood, W., General Chemistry Principles and Modern Applications,
`6"" Ed.. pp. 656-57 (1993) (TevaTRE600397 1-4)
`
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`®
`
`Priorart disclosed or cited during prosecution of the ’007, °137, and *694 patents.
`
`Teva expressly reserves the right to modify and/or supplement the above list at any time as
`
`necessary and/or as discovery progresses.
`
`The following chart
`
`incorporates the analysis set forth above and identifies where
`
`specificalfy in each aileged item of prior art each limitation of each asserted claim is found:
`
`i A method of selectively killing
`Anticipation: Claim 1 of the
`“007 patent
`is invalid,
`| gram negative
`bacteria
`and
`because tt is anticipated by European Patent Application
`i inhibiting the growth of gram
`EP 0347243A1 (SEP ?243”) or obvious over EP °243 in
`i positive
`bacteria
`in
`a
`view of Sterile Diluent For Flolan and/or knowiedge of
`| pharmaceutical
`preparation
`one of ordinary skill in the prior art.
`i comprising
`an
`active
`agent
`i selected
`from the
`group
`| consisting of treprostinil
`and
`| treprostinil sodium, the method
`i comprising supplying the active
`| agent with a buffer comprising
`i glycine and having a pH of
`: greater than 10 with lowbuffer
`| capacity.
`
`thus,
`EP °243 issued on December 20, 1989, and is,
`102(b) prior art. EP °243 patent disclosed and claimed
`medicaments
`for
`the
`treatment
`of
`pulmonary
`hypertension that could be used subcutaneously or
`intravenously. EP °243, 9] 22,25. Example 1 discloses
`the combination of treprostini] and a “glycine buffer”
`with a pH of 10.5.
`
`
`
`EP °243 further describes the use of buffer solutions with
`treprostinil
`to treat pulmonary hypertension. EP °243
`concludes that treprostinil used with a glycine buffer
`solution of greater than pH 10 “was found to reduce
`hypoxia-induced increase in pulmonaryarterial pressure
`and pulmonary vascular
`resistance in a dose-related
`manner without appreciably affecting cardiac output or
`heart rate.” Za. at 9] 32-34.
`
`EP °243 discloses that “sterile” acqueous solutions are
`preferred and that “[s]uch preparations may conveniently
`be prepared by admixing the compound with water or a
`glycine buffer and rendering the resulting solutionsterile
`and isotonic with the blood.” fd. at25. Therefore, the
`pharmaceutical preparation of EP ’243 inherently inhibits
`growth of gram positive bacteria and,
`if given te a
`person, wili
`inherently kill gram negative bacteria.
`66
`Therefore, EP
`7243
`discloses
`“a
`pharmaceutical
`preparatio’’
`or
`“pharmaceutical
`composition”
`comprising “treprostinil”
`and “a buffer comprising
`|
`oiigycineandhavingapHofgreaterthan10°withthe|
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`
`
`inherent qualities described in the claims. Moreover,
`having a low buffer capcity is an inherent property of
`sterile solutions with a high pHthat are isotonic with the
`blocd and are intended to be given to humans, as the pH
`of the pharmaceutical preparation should quickly adjust
`to the pH of blood, which is substantially lower than pH
`of 10. fd.
`
`
`
`Obviousness: If EP °243 does not anticipate the ’007
`patent, °007 patent is invalid as obvious over EP °243
`patent
`in view of the commercial embodiment Sterile
`Diluent for Flolan®. Flolan® is a third-party competitive
`product, containing epoprostenol, which was approved in
`1995 for treating pulrnonary hypertension. Flolan® is a
`powder that must be reconstituted with “Sterile Diluent
`for Flolan” (SDF”). SDF is a solution containing the
`amino acid glycine and having a pH greater than 10 that
`physicians or patients may use to dilute Flolan prior to
`intravenous infusion. The use of SDF (or a buffer such
`as SDF) was described, for example,
`in 1999 Flolan®
`label and U.S. Patent No. 4,335,139'°.
`SDF was
`available more than 1 year prior to the earliest priority
`date of the ’007 patent and is 162(b) prior art to the °007
`patent.
`
`A person ofordinary skill in the art would have found it
`obvious to combine Remodulin in combination with
`SDF, based on the teachings of EP °243,
`the existing
`knowledge and use of SDF, and knowledge of one of
`ordinary skill in the art, with a reasonable expectation of
`success at arriving at the claimed invention. KSR Int’
`Ca. v. Telefiex Ine., 550 U.S. 398, 421 (2007). As ofthe
`priority date of the “007 patent, Remodulin (treprostinif)
`was the commercially-available treprostinil product, and
`SDF was the only commercially-availabie glycine buffer
`with a pH of 10.5, already in use with another pulmonary
`eee fypertensionmedication.Andasthedistrictcourtinthe.
`
`“TS. Patent No. 4,335,139 was cited by the Examiner during the prosecution of U.S. Patent No. 8,658,694 and
`appcars on the facc of 2000 Flolan® label.
`The °139 patent discloscs the use of a prostacyclin with “a
`pharmaceutically acceptable buffer having a pH value ofat least 9 and based on an amino acid as the principal
`buffering acid in the buffer.” °139 patent, col. 1, lines 38-45. “Such a solution and all solutions hereinafter referred
`to are, for medicinal purposes,
`to be understood to be sterile solutions.” fa at col. 2, lines 4-6.
`“Glycine” is
`specifically disclosed as an amine acid of the buffer.
`/¢@ at Example 1. Example 7 specttically discloses a sterile
`diluent for injection of a prostacyclin, which contains glycine and has a pH of 10.5. The 2000 Flolan label
`incorporated byreference the °139 patent as covering Flolan®and SDF.
`
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`
`
`related case, UTC v. Sandoz, 12-CV-01617, 13-CV-316
`(D.NJ. 2014), expressly found, this combination would
`meet all of the asserted claims of the °007 patent.
`(Decision at 73.) UTC’s expert in the related Sandoz
`matter, Dr. Michael Miller, admitted at trial that a person
`of ordinary skill
`in the art,
`seeking to practice the
`invention disclosed and claimed in EP ’243, could easily
`have done so by combining Remodulin and Sterile
`Diluent for Flolan, both of which were commercially
`available products as of the priority date for the °007
`patent.
`
`A person of ordinary skill in the art also would have been
`motivated to use treprostinii with a high pH buffer
`comprising glycine with a reasonable expectation of
`success in inhibiting bacterial growth or reducing the
`occurrence of blood stream infections.
`
`
`
`The use of SDF resulted in a high pH glycine buffer
`solution that was sterile, antibacterial and anti-infective.
`Moreover, it was well-knownin the prior art that glycine
`is an amino acid that has antibacterial properties. See e.g.
`Foegeding P.M. et al, “Chemical Food Preservatives,”
`Ch.
`47
`at
`825
`in Disinfection, Sterilization
`and
`Preservation 4" Ed. 1991: Hammes et al, “Mode of
`Action
`of Glycine
`on
`the
`Biosynthesis
`of
`Peptidogiycoan,” 3. Bacteriology, Vol. 116, No. 2 pp.
`1029-1053
`(1973), Strominger
`et
`al.,
`“Nucleotide
`Accumulation Induced in Staphylococcus aureus by
`Glycine,” J. Bacteriology, Vol. 89, No, 4 pp. 1124-1127
`(1965). Therefore, as the following prior art explains, as
`of the priority date, it was also known that a solution in
`an alkali environment (high pH solutions) with glycine
`will have bactericidal antiinfective effects.
`See, e.g.,
`Mendonca, et al, “Destruction of Gram-Negative Food-
`Borne Pathogens by High pH Involves Disruption ofthe
`Cytoplasmic Membrane,: Applied and Environmental
`Microbiology, val. 60, No. Tl, p. 4009-4014 (1994).
`(“Mendonca”) (disclosed during the prosecution of the
`
`"007 “Growth=ofpatent), Crowther et al,
`
`
`
`
`Microorganisms in Propofol, Thiopental, and a
`i:1
`Mixture Of Propofcl and Thiopental,” Anesth. Analg.,
`82:
`AT5-478
`(1996)
`Crowther’)
`(TEVATRE0004034-7),
`and
`Sigueira
`et
`al,
`peeeeRRERREREOREe Lieenereeeeee
`Mechanisms
`of
`antimicrobial
`activity
`of
`calcium
`
`
`
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`
`
`hydroxide: a critical review,” Intern. Endodontic F., 32,
`pp. 361-369, (1999) (“Siqueira) (TEVATRE6004298-
`306}.
`
`
`
`that glycine and high pH
`Consistent with the fact
`solutions have known antibacterial properties, the prior
`art describes glycine buffer solutions that have high pH
`for use in pharmaceutical formulations. See U.S. Appln.
`No. 10/137,331 (disclosed during prosecution of the ’007
`patent);
`1999
`Flolan
`Package
`Insert
`(TEVATRE0004281-84) (disclosing the use of SDF
`and SDF’s qualities); EP °243 (TEVATRE0004270-
`80}
`(discussed in more detail
`above); U.S. Patent
`Publication No. 2005/G165110 Guly 2005) by Wadeetal.
`at
`[0030] (Wade 2005”) (TEVATRE0004213-218);
`and The 2005 Physicians’ Desk Reference for Flolan®
`{epoprostenol
`sodium for
`injection)
`(“2005 PDR”)
`(TEVATRE0003991-6) (disclosing SDF,
`its use, and
`qualities).
`Indeed, as discussed earlier,
`the prior art
`specifically describes, suggests, and combines treprostinil
`with a high pH glycine buffer solutions for use in
`pharmaceutical compositions for humans. See EP °243;
`Wade 2005. As is evident from thee disclosures, a
`person of ordinary skul would have been motivated to
`address possible complications from bacterial infections
`when treprostinil
`is
`administered intravenously,
`as
`suggested by the use of SDF and the disclosures of EP
`243,
`
`A solution having “a low buffer capacity,” if not
`inherent, also would have been known to a person of
`ordinaryskill in the art.
`(Claims 1-5, 7-10, 16-17, and 21
`also require that the glycine buffer used in the claimed
`methods have a low buffer capacity, sc this analysis
`applies to the other claims with equal force.) The ’007
`patent states that “the buffer capacity should be lowto
`avoid pH changes in the bicod upon infusion.” Cel. 2,
`lines 34-35.
`SDF inherently possesses this limitation.
`Moreover, 1t would have been obvicus to a person of
`ordinary skill in the art that it is important to maintain the
`proper
`pH of
`blood
`to
`avoid
`possible
`severe
`complications. See e.g. Petrucci, R. and Harwood, W.,
`General Chemistry Principles and Modern Applications,
`6" Ed., 1993, pp. 656-57 (explaining that the normal pH
`|
`cLofbloodis7.4andincreasedpHofbloodcanleadto|
`
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`Teva’s Amended Contentions
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`Highly Confidential
`
`severe vomiting and hyperventilation). Consequently, it
`would have been obvious to a person of ordinary skill to
`formulate the high pHbuffer solution with a low buffer
`capacity,
`so that
`it would be safe and avoid any
`complications based on changes of biood pH when the
`treprostinil solution is administered. See alse EP °243 at
`
`q P
`
`forth its contentions concerning
`laintiff has not set
`secondary considerations in this case. H Plaintiff relies
`on any secondary considerations of non-obviousness,
`Teva reserves the right to supplement its contentions.
`Dependent claim 2 incorporates the method of claim 1;
`therefore, the contentions incorporate the analysis from
`claim 1
`in its entirety. Claim 2 further specifies that the
`active agent
`is
`treprostinil
`sodium.
`The prior art
`specitically describes
`the use of glycine buffered
`solutions with treprostinil. EP °243; Wade 2005 [0030].
`Also, the 2006 Remedulin Package Insert describes the
`_useoftreprostinilastheactiveingredient.
`Dependent claim 3 incorporates the method of claim 1,
`therefore the contentions incorporate the analysis from
`claim 1
`in its entirety. Dependent claim 3
`further
`specifies that the buffer to contain sodium hydroxide.
`SDF contained sodium hydroxide. Moreover, the 1999
`Flolan Package Insert, the 2005 PDR, and Calbicchem
`describes sodium hydroxide as a basic agent that can be
`used to adjust the pHofa solution and can be used in the
`an eeennneen
`glycine butter solution.
`Dependent claim 4 incorporates the method of claim 1,
`therefore the cantentions incorporate the analysis from
`claim 1
`in its entirety. Dependent claim 4 further
`requires the buffer solution to have a pH between about
`10 to about 12. The 1999 Flolan Package Insert and the
`2005 PDR, and Calbiochem describe the pH of the
`glycine buffer from 10.2 to 10.8, and EP °243 describes
`such a formulation at Example 1. Therefore,
`the pH
`range claimed herein is disclosed in the prior art.
`Dependent claim 5 incorporates the method of claim I;
`therefore, the contentions incorporate the analysis from
`claim 1
`in its entirety. Dependent claims 5 further
`requires the buffer solution to have a pH between about
`10.2 to 10.8. The 1999 Ficlan Package Insert and the
`2005 PDR, and Calbiochem describe the pH of the
`I glycinebufferfrom10.2to10.8,andEP7243describes|
`
`| The method ofclaim 1, wherein
`| the active agent
`is treprostinil
`| sodium
`
`The method ofclaim 1, wherein
`ithe buffer
`further
`comprises
`| sodium hydroxide.
`
`The method of claim i, wherein
`ithe buffer has a pH between
`about 10 to about 12 with low
`' buffer capacity.
`
`| The methodof claim 4, wherein
`ithe buffer has a pH between
`| about 10.2 to about 10.8 with
`: low buffer capacity.
`
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`Highly Confidential
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`
`' The method of claim 1 further
`i comprising
`injecting
`the
`| pharmaceutical preparation into
`a mammal in needthereof.
`
`
`
`
`
`
` such a formulation at le |. Therefore,
`the pH
`
`
`
`range claimed hereinis disclosed in the prior art.
`
`
`| The methodofclaim 1, wherein
`Dependent claim 7 incorporates the method of claim 1;
`
`
`i the active agent is supplied at a
`therefore, the contentions incorporate the analysis from
`
`| concentration
`between
`about
`claim 1
`in its entirety. Dependent claim 7 further
`
`
`16.001 mg/mL to
`about
`1
`specifies the active agent
`to be at
`a concentration
`
`
`
`i mg/L.
`between about ¢.00] mg/mLto about 1 mg/mL. EP 243
`
`
`
`and the 2006 Remodulin Package Insert at dosing
`
`
`instruction disclose concentrations that specifically cover
`
`
`this ranges. F.g.,EP "243 at 5.
`
`
`
`
`Dependent claim & incorporates the method of claim 1;
`i The method of claim 2, wherein
`
`
`| the
`treprostinil
`sodium is
`therefore, the contentions incorporate the analysis from
`
`i supplied
`at
`a
`concentration
`claim 1
`in its entirety. Dependent claim 8
`further
`
`i between about 0.004 mg/mLto
`specifies the active agent
`to be at a concentration
`
`| about 0.13 mg/mL.
`between about 0.