.:
`
`-4-
`
`or a physiologically acceptable salt thereof for the reduction ef the risk in the level of iron burden
`
`in the heart ef heart disease in heavily transfused patients ha¥iftg experiencing iron overload of
`
`the heart, slieh as i:A thalassemia er the like eemprising an effeetive ameoot ef deferiprene er a
`
`13hysielegieally aeeeptaele salt thereef said therapeutic amount being sufficient to tf0tK reduce
`
`iron burden in the heart and the resulting iron induced cardiac disease nermally esseeieted with
`
`iren e·,rerleeEl.
`
`11. (currently amended) A method of preventing the risk ef heart disease in heavily transfused
`
`patients ha¥iftg risking iron overload of the heart, s1:1eh es in tha-lassemia er the like comprising the
`
`administration of a therapeutically effective amount of deferiprone or a physiologically acceptable
`
`salt thereof sufficient to tf0tK prevent iron induced cardiac disease aeRHelly asseeiateEl '>'lith ifen
`
`e"'erleaEl.
`
`12. (currently amended) A method of stabilizing the risk ef heart disease in heavily transfused
`patients having iron overload, Slieh as in thalassemia er the like comprising the administration of a
`
`therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof sufficient
`
`to treat iron burden in the heart normally associated with induced cardiac disease aermally
`
`asseeieted with iree everleael.
`
`13. (currently amended) A method of reducing the risk ef the iron burden in the heart associated
`
`with heart disease in heavily transfused patients having iron overload, SliSR as ia thalassemia er the
`
`ttke-comprising the administration of a therapeutically effective amount of deferiprone or a
`
`physiologically acceptable salt thereof sufficient to treat reduce the iron burden of the heart
`
`normally associated with iron induced cardiac disease eeffftally asseeiated 'Nith irea everlead.
`
`18. (currently amended) A pharmaceutical composition for
`
`iron
`
`induced cardiac disease
`
`comprising a therapeutically effective amount of the iron chelator deferiprone or physiologically
`
`acceptable salt thereof for the prevention, treatment, or reversal of heart disease in heavily
`
`transfused patients he¥ffig risking or experiencing an iron overload condition of the heartl
`
`eemprisi:Ag an effeetive ame1:1at ef deferiprene er e physielegieelly aeeeptaele salt thereef said
`
`therapeutic amount being sufficient to prefereAtially reduce the iron stores in the heart and in
`
`eemparisea preference to the iron stores in less critical organs/tissue in the body.
`
`22. (currently amended) A method of treatinWf're•>'entie~er reversiag heart disease in a heavily
`
`transfused patient having an iron overload condition of the heart comprising administering to the
`
`patient a therapeutically effective amount of deferiprone, or a physiologically acceptable salt thereof
`
`
`221 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`r ,,
`
`..
`
`-5-
`
`in order to prefereRtielly reduce the iron stores in the heart in eemplH'iseR preference to less critical
`
`organs/tissue in the body.
`
`23. (currently amended) A method of tTeatiawpreventinyer reversing heart disease in heavily
`
`transfused patients having an iron overload condition of the heart comprising administering to the
`
`patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof
`
`to prefereatially re6tiee chelate the iron stores in the heart in eomparisoe preference to the iron
`
`stores in less critical organs/tissue in the body.
`
`24. (currently amended) A method of treatiawpreveatiawer reversing heart disease in heavily
`
`transfused patients having an iron overload condition of the heart comprising administering to the
`
`patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof
`
`to prefereRtially reduce the iron stores in the heart in eemparisoa preference to the iron stores in less
`
`critical organs/tissue in the body.
`
`25. (currently amended) A method of treatment, prevention, or reversal of heart disease in a heavily
`
`transfused patient having an iron overload condition of the heart comprising administering to the
`
`patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof
`
`for the direct prefereatial reduction/removal of. irea (fer enllffij3le intracellular iron~ stores in the
`
`heart.
`
`26. (currently amended) A method to prevent/treat/reverse the occurrence of iron-induced cardiac
`
`disease in heavily transfused patients with an iron overload condition seeh as tha:lessemia er the
`
`ltke, comprising administering to said patient a therapeutically effective amount of deferiprone or a
`
`physiologically acceptable salt thereof, wherein deferiprone's efficacy is cardio preferential when
`
`compared with its ability to lower total iron stores in the body.
`
`30. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 flH:thet:
`
`eefflprisiag the wherein eeti·1e ingreclieat deferiprone or a physiologically acceptable salt thereof~
`
`administered orally for preventing the risk of heart disease in patients having iron overload.
`
`31. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 fw:tftef
`
`eemprisiRg the wherein aetive iagreclieat deferiprone or a physiologically acceptable salt thereof~
`
`administered orally for stabilizing the risk of heart disease in patients having iron overload.
`
`
`222 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`,
`
`-6-
`
`32. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 fHfthef
`
`eoffifJrisiag the wherein aeti'le iagredieat deferiprone or a physiologically acceptable salt thereof~
`administered orallv for reducing the risk of heart disease in patients having iron overload.
`
`33. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 fHfthef
`eoffifJrisiag E1B oml dosage foRH of wherein deferiprone or a physiologically acceptable salt thereof
`
`is present is an oral dosage form with other excipients.
`
`35. (currently amended) The method of claims 1, 2, I 1, 12, 13, 22, 23, 24, 25 and 26 fHfthef
`eOffifJAsi:Bg daily wherein the administration frequency to the patient of an amount of deferiprone
`or a physiologically acceptable salt thereof is daily and substantially in the range of up to 150mglkg
`
`to the f!atieRt. per kilogram of body weight.
`
`37. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 fHfthef
`eoffiflriSif1g wherein the administration frequency to the patient of a 0aily dosage amount of
`deferiprone or a physiologically acceptable salt thereof is daily and substantially in the range of up
`
`to 125 mW-kg to the patieflt. per kilogram of body weight.
`
`39. (currently amended) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 ftH:thef
`
`eomprisiag wherein the administration frequency to the patient of a 0aily dosage amount of
`deferiprone or a physiologically acceptable salt thereof is daily and substantially in the range of
`25mglkg to 75m~g to the patient. per kilogram of body weight.
`
`41. (original) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone is
`
`administered in a manner selected from the group of intravenously, transdermally, rectally, orally,
`
`bucally, or aurally.
`
`43. (original) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone is
`administered orally.
`
`45. (currently amended) The method of claims l, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein the
`
`dosage form deferiprone or a physiologically acceptable salt thereof is in a sustained release
`
`formulation.
`
`
`223 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-7-
`
`47. (original) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone has
`
`a cardio preferred/selective function when compared to desferrioxamine or other alternative chelating
`
`agents utilized in patients suffering iron overload.
`
`49. (original) The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone is
`
`administered in addition to desferrioxamine.
`
`51. (cancelled)
`
`52. (cancelled)
`
`53. (cancelled)
`
`54. (cancelled)
`
`55. (currently amended) The effeetive theFapeutie ameunt composition of claims 8, 9, 10 and 18
`
`fui:ther eomprisieg wherein said composition is administered to the patient daily adnMnislfatioa of
`
`an amel:lflt efdeferiproae er a physielegieally aeeeptaele salt thereof and substantially in the range of
`
`up to l SOmg/kg te the-patient-: per kilogram of body weight.
`
`56. (currently amended) The effeeti·1e tl=lerape1:1tie amelmt composition of claims 8, 9, 10 and 18
`
`hilther eemprisiag a<iministratiea of a wherein said composition is administered to the patient
`
`daily dosage amei:mt of deferipreee er a flhysielogieally aeeeptaele salt thereof and substantially in ·
`
`the range of up to 125 mg/kg to t:he patie:at. per kilogram of body weight.
`
`57. (currently amended) The effeetive thera13e1:1tie amel:lflt composition of claims 8, 9, 10 and 18
`
`further eomprisiHg adm:ifl:istratie:a of a wherein said composition is administered to the patient
`
`daily elosage amoUHt of eleferiproHe er a pl=lysielogieally aeeeptaelo salt thereof,!!!!! substantially in
`
`the range of 25mg4Eg to 75mglkg to the patieat. per kilogram of body weight.
`
`58. (currently amended) The effeetive ther8f>eutie amel:lflt composition of claims 8, 9, 10 and 18
`
`wherein deferipre:ae the composition is administered in a manner selected from the group of
`
`intravenously, transdennally, rectally, orally, bucally, or aurally.
`
`59. (cancelled)
`
`
`224 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-8-
`
`60. (currently amended) The effeeti·,ze taerQf3e1:1tie a.me1:1Rt composition of claims 8, 9, 10 and 18
`
`wherein the desage furai composition is in a sustained release formulation.
`
`61. (currently amended) The effeeti¥e them13e1:1tie a.me1:1At composition of claims 8, 9, 10 and 18
`
`wherein deferitireRe said composition has a cardio preferred/selective function when compared to
`
`desferrioxamine or other alternative chelating agents utilized in patients suffering iron overload.
`
`62. (currently amended) The effeetive thefQf3e1:1tie eme1:1At composition of claims 8, 9, 10 and 18
`wherein deferitireRe the composition is administered in addition to desferrioxamine.
`
`
`225 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`This Page Is Inserted by IFW Operations
`arid is not a part of the Official Record
`
`. .
`
`.
`
`BEST AVAILABLE IMAGES
`
`Defective images within this document are accurate representations of
`the original documents submitted by the applicant.
`
`Defects in the images may include (but are not limited to):
`
`• BLACK BORDERS
`
`• TEXT CUT OFF AT TOP, BOTTOM OR SIDES
`
`• FADEDTEXT
`
`•
`
`ILLEGIBLE TEXT
`
`• SKEWED/SLANTED IMAGES
`
`• COLORED PHOTOS
`
`• BLACK OR VERY BLACK AND WHITE DARK PHOTOS
`
`• GRAY SCALE DOCUMENTS
`
`IMAGES ARE BEST AVAILABLE COPY.
`
`As rescanning documents will not correct images,
`please do not report the images to the
`Image Problem Mailbox.
`
`
`226 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`REMARKS
`
`-9-
`
`The Examiner states that the Abstract of the disclosure is objected to because it does not
`
`appear on a separate page without extraneous subject matter present. A revised abstract on a separate
`
`page is attached to this response for the Examiner's consideration.
`
`Claims l, 2, 8-13, 18, 25, 30-32, 33, 35, 37, 39, 45, 54, 55-59, 60 and 62 now stand rejected under 35
`
`U.S.C. 112, second paragraph, as being indefinite for allegedly failing to particularly point out and
`
`distinctly claim the subject matter which applicant regards as the invention.
`
`These claims therefore have been revised consistent with the Examiner's suggestions on pages 3 and
`
`4 of his report and full reconsideration is requested.
`
`With respect to claims 55, 56 and 57 applicants have amended these claims to more specifically
`identify that the composition is administered in the specified amount per kilogram of body weight of
`
`the patient. This approach further follows a well known convention present in the patent and peer
`
`reviewed literatures, for example in Hoffbrand cited by the Examiner. Full reconsideration is
`
`therefore requested.
`
`Applicant will now provide the Examiner with further general discussion and perspective
`
`information.
`
`In conditions of iron overload, such as those with the genetic blood disorder,
`
`thalassemia major, patients develop iron-induced organ damage as a result of chronic and frequent
`
`blood transfusions. Blood transfusions are necessary to sustain life because of the inability of the
`
`body to maintain an adequate hemoglobin level due to its defective formation and rapid degradation.
`However, the frequent blood transfusions (every 2-3 weeks), result in massive iron loading in the
`
`body, with a non-homogeneous distribution of the iron among the tissues. Typically, the liver will
`
`accumulate the most iron and various other organs, glands and other tissues much Jess. Animal
`studies suggest that the ratio of liver iron to heart iron per gram of tissue is approximately 10: l. Yet,
`
`the primary cause of death in patients with thalassernia is due to iron-induced heart disease, not liver
`
`disease, with about 70% of the patients dying from iron-induced cardiac disease.
`
`Deferoxamine was the first iron chelator to be approved for clinical use in conditions of iron
`
`overload. The chronic use of deferoxamine resulted in a substantive decrease in the total body
`
`burden of iron and a decrease in morbidity and a prolongation of life. The use of deferoxamine was
`reported to facilitate not only the removal of iron from the body, but also the survival without iron(cid:173)
`
`induced cardiac disease (Olivieri NF, Nathan DG, MacMillan JH, et al. "Survival in medically
`treated patients with homozygous -thalassemia", N Engl J Med 1994;331:574-578).
`
`
`227 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`.·
`
`-10-
`
`One of the first well-described and detailed studies on the use of deferiprone in thalassernia patients,
`
`spanning a period of several years, was published in the New England Journal of Medicine in April
`1995 (Olivieri NF, et al "Iron-chelation therapy with oral deferiprone in patients with thalassemia
`
`major", 332(14):918-22). The article reported deferiprone reduced the total body burden of iron. as
`
`judged by liver iron concentrations and serum ferritin concentrations. The response of the patients
`
`led the author to conclude {precise wording: Our data provide direct evidence of the efficacy of
`
`deferiprone for the treatment of iro11 overload i11 patie11ts with tlialassemia major. Deferipro11e
`
`decreases body iro11 conce11tratio11s and mai11tai11s them at levels below those associated with the
`
`complications of iron overload). Although the use of deferiprone seemed to be a promising
`
`alternative to deferoxarnine to lower total body burden of iron, there was no evidence of a unique
`cardio protective effect. In fact, an accompanying editorial by Dr. David Nathan made it clear that,
`
`while the data were encouraging, the lack of evidence that deferiprone had any ability to remove iron
`
`from the heart and thus increase survival, raised questions as to its utility: "Not enough is known
`
`about the pharmacologic properties of deferiprone. Will the low levels of drug that remain in the
`
`plasma continue to chelate free iron and thereby protect heart-muscle membranes, or will the sma/J
`
`but highly toxic pool of free iron remain or return to high levels between doses to do its damage?
`
`Over time, will the drug's ability to be absorbed prove to be a two-edged sword because it can also
`
`permeate the cell membranes of vital organs such as the kidney, with toxic effects? " (Nathan D. G.
`
`A11 orally active iron chelator. N.E11glJ.Med. 332 (14):953-954, 1995).
`
`Subsequently, several articles appeared in the medical literature indicating that the use of deferiprone
`was less effe.ctive than the use of the other iron chelator, deferoxarnine, in removing iron from the
`body. This was assessed primarily by liver iron concentrations and, in some cases, by serum ferritin
`
`concentrations over time. Thus, it was expected that, on the basis of the ability to reduce the iron
`body burden alone, one would reasonably predict lesser benefit from deferiprone in terms of survival
`related to iron-induced cardiac disease. That is, if any potential cardio-protective effect was solely
`
`related to the ability of an iron chelator to remove iron from the body, as was understood to be the
`
`case for deferoxarnine, then deferiprone should have less effect than deferoxamine as a cardio(cid:173)
`
`protectant.
`
`In 1998 (Olivieri N. F., B11ta11y J., Te111pleto11 D. M., and Britte11/ia111 G. M. Cardiac Failure and
`
`Myocardial Fibrosis in a patie11t with Tliallassemia Major (TM) Treated with Long-Tem
`
`Deferipro11e. Blood 1998; 92:532a.) this same author published a report at the annual meeting of
`
`ASH, that she believed deferiprone had been responsible for the decline in the cardiac function of a
`
`patient and that this decline was associated with myocardial fibrosis as well. Clearly, the only
`
`evidence that had been in the literature at that time, suggesting, if at all, that there might be some
`
`
`228 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-11-
`
`benefit of deferiprone affecting the heart, was clearly rejected by the very person who published that
`
`information and in 1998 she had come to the conclusion that the opposite was the case.
`
`The data that provided the evidence of the preferential cardio-protection of deferiprone was the work
`
`that Applicant conducted in Torino, which formed the basis for this application, to evaluate the
`
`response of all patients in the same center treated by the same clinical team in the same manner with
`
`the exception that some patients received deferiprone and some deferoxamine. That study revealed
`
`that there was a preferential effect in the deferiprone-treated patients in protecting the heart, both
`
`from iron-induced cardiac disease as well as survival, that could not be explained by the removal of
`
`iron from the body alone. That is, the patients receiving deferiprone did not excrete more iron from
`
`the body than did patients receiving deferoxamine, yet clearly there was a preferential cardiac benefit
`
`in deferiprone-treated patients. These data clearly demonstrate that there was a direct benefit to the
`
`heart obtained from using deferiprone that was not simply due to the removal of iron from the body,
`
`and was not predictable based on the potency of deferiprone compared to deferoxamine.
`
`It has been reported that increased iron overload results in an increase in iron-induced cardiac
`
`damage. It has also been reported that the removal of iron from the body is likely to decrease that
`
`risk. Thus one reasonably should conclude that an iron chelating agent which induces a greater
`elimination of iron from the body, should also exhibit a greater decline in the risk of iron-induced
`
`cardiac damage. That, however, is not the case with deferiprone. The decline in body iron burden
`
`with this drug compared to deferoxamine. as evidenced by changes in liver iron concentrations. the
`
`most extensive site of iron storage in the body, would predict that deferoxamine would have had a
`
`greater cardio-protective effect than deferiprone. Since these data from the Torino study demonstrate
`
`exactly the opposite effect, one can only conclude there is a preferential effect of deferiprone, not
`
`predicted by the removal of iron from the body alone. Thus the discovery is unpredicted from the
`
`literature.
`
`Claims 8, 9, 10, 18, 51-59 now stand rejected under 35 U.S.C. 102(b) as being allegedly anticipated
`
`by any one of Olivieri et al., Hoffbrand et al. (Examiner cit. Ref. "U") or Hoffbrand et al. (Examiner
`
`cit. Ref. "V") who each purport to teach as alleged by the Examiner, an effective therapeutic amount
`
`of deferiprone at a dosage of 75mg/kglday.
`
`Claims 1, 2, 8-13, 18, 22-26, 30-33, 35, 37, 39, 41, 43, 45, 47, 49 and 51-62 now stand rejected under
`
`35 U.S.C. 103(a) as being allegedly unpatentable over Lai (US Patent No. 5,922,761) who purports to
`
`teach methods for the reduction of free iron levels in a subject in which a dithiocarbarnate containing
`
`composition iron chelator is administered, but not deferiprone.
`
`
`229 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-12-
`
`Before commencing any rebuttal with reference to any alleged prior art issues the Examiner is
`
`respectfully directed towards the following exerpted case law from which Applicant will draw
`
`liberally.
`
`ANTICIPATION
`
`The following excerpts of U.S. case law represent Applicant's understanding of the test for novelty
`
`and obviousness.
`
`In Hybritech Inc. v. Monoclonal Antibodies. Inc., 802 F.2d 1367, 231 U.S.P.Q. 81, 90 (Fed. Cir.
`1986) ("It is axiomatic that for prior art to anticipate under § 102 it has to meet every element of the
`
`claimed invention, and that such a determination is one of fact.").
`
`In re Donohue, 766 F.2d 531, 226 U.S.P.Q. 619, 621 (Fed. Cir. 1985) ("an anticipation rejection
`
`requires a showing that each limitation of a claim must be found in a single reference, practice, or
`
`device.").
`
`In Atlas Powder Co. v. E.I. du Pont De Nemours & Co., 750 F .2d 1569, 1574, 224 U.S.P.Q. 209, 411
`
`(Fed. Cir. 1984) ("exclusion of a claimed element from a prior art reference is enough to negate
`
`anticipation by that reference").
`
`In Tights, Inc. v. Acme-McCrary Corp., 541, F.2d 1047, 191 U.S.P.Q. 305 (4th Cir. 1976); Saf-Gard
`
`Prods .. Inc. v. Service Parts. Inc., 532 F.2d 1266, 190 U.S.P.Q. 455 (9th Cir. 1976); Shanklin Corp. v.
`
`Springfield Photo Mount Co., 521 F.2d 609, 187 U.S.P.Q. 129 (1st Cir. 1975) ("To anticipate under
`
`section 102, a prior art reference must disclose all the elements of the claimed invention or their
`
`equivalents functioning in essentially the same way.").
`
`In re Beno {1985) 768 F.2d 1340, 226 U.S.P.Q. 683 (Fed. Cir. 1985) a prior art patent or published
`
`application is a reference only for that which it teaches.
`
`/11 re Sun, 31USPQ2d 1451, 1453 (Fed. Cir. 1993) (unpublished)
`
`Under section 102(b), anticipation requires that the prior art reference disclose, either expressly or
`
`under the principles ofinherency, every limitation of the claim ....
`
`
`230 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`.·
`
`-13-
`
`But to be prior art under section 102(b), a reference must be enabling .... That is, it must put the
`claimed invention in the hand of one skilled in the art ... . The examiner bears the burden of
`
`presenting at least a prima facie case of anticipation.
`
`Hellfu: Ltd. v. Blok-Lok, Ltd., 54 USPQ 2d 1299, 1304 (Fed. Cir. 2000)
`
`"[E]ven if the claimed invention is disclosed in a printed publication, that disclosure will not suffice
`
`as prior art if it was not enabling." Donohoe, 766 F.2d at 533, 226 USPQ at 621.
`
`In re Wilder, 166 USPQ 545, 548 (C.C.P.A. 1970)
`
`Simply stated, a prior publication or patent description will be considered as anticipatory when its
`
`disclosure is at once specific and enabling with regard to the particular subject matter at issue ....
`However, such disclosure may yet be held not to legally anticipate the claimed subject matter if it is
`
`found not to be sufficiently enabling, in other words, if it does not place the subject matter of the
`
`claims within "the possession of the public."
`
`Ciba-Geigy Corp. v. Alza Corp. , 37 USPQ 2d 1337, 1341 n.3 (Fed. Cir. 1995) (unpublished)
`
`An anticipatory reference must be enabling, see Akzo N. V. v. United States Int'/ Trade Comm'n, 808
`
`F.2d 1471, 1479, 1 U.S.P.Q.2D (BNA) 1241, 1245 (Fed. Cir. 1986), cert. denied, 482 U.S. 909, 96 L.
`
`Ed. 2d 382, 107 S. Ct. 2490 (1987), so as to place one of ordinary skill in possession of the claimed
`
`invention. In re Spada, 911 F.2d 705, 708, 15 U .S.P.Q.2D (BNA) 1655, 1657 (Fed. Cir. 1990); see
`
`Seymour v. Osborne, 78 U.S. 516, 555, 20 L. Ed. 33 (1870) ("The knowledge supposed to be derived
`
`from the publication must be sufficient to enable those skilled in the art or science to understand the
`
`nature and operation of the invention.").
`
`OBVIOUSNESS
`
`The traditional test enunciated in Graham vs. John Deere Company 383 U.S. 1, 148 U.S.P.Q. 459
`
`1966, for Section 103 nonobviousness requires the fact finder to make several determinations. The
`
`test provides that the scope and content of the prior art be determined, the differences between the
`
`prior art and the claims at issue be ascertained, and the level of ordinary skill in the pertinent art be
`
`resolved. Thus, the patentability of the claims at hand must stem from the fact that the specific
`
`combination of the claimed elements was not disclosed in the prior art and the additional allegation
`
`that the specific combination of claimed elements was nonobvious to one of ordinary skill in the art.
`
`
`231 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`..
`
`-14-
`
`Clearly, the prior art does not suggest or provide any reason or motivation to make such a
`
`modification as purported by the Examiner. With reference to In Re: Regal, 526 F. 2d 1399, 1403 n.
`
`6, 188 USPQ 136, 139 n. 6 (CCPA 1975).
`
`"There must be some logical reason apparent from positive, concrete evidence of
`
`record which justifies a combination of primary and secondary references".
`
`•
`
`In Re: Geiger, 815 F. 2d 686, 688, 2 USPQ 2d 1276, 1278 (Fed. Cir. 1987) (obviousness can not be
`established by combining pieces of prior art absence . some "teachings, suggestion, or incentive
`
`supporting the combination"): In Re: Cho. 813 F. 2d 378, 382, 1 USPQ 2d 1662, 1664 (Fed. Cir.
`
`1987)("discussing the Board's holding that the artisan would have been motivated to combine the
`
`references").
`
`Therefore, it Applicant's view there is no evidence of motivation in the prior art, either within the
`
`references themselves, or knowledge generally available to one of ordinary skill in the art, to make
`
`the purported changes suggested by the Examiner to arrive at the claimed subject matter.
`
`Respectfully, the Examiner is creating a 20/20 hindsight reconstruction using Applicant's invention
`
`as a blue print to allegedly find elements of Applicant's combination in the prior art. This is not
`
`permissible as set out below.
`
`In re Oetiker, 24 USPQ 2d 1443, 1446 (Fed. Cir. 1992)
`
`The combination of elements from non-analogous sources, in a manner that reconstructs the
`
`applicant's invention only with the benefit of hindsight, is insufficient to present a prima facie case of
`
`obviousness. There must be some reason, suggestion, or motivation found in the prior art
`
`whereby a person of ordinary skill in the field of the invention would make the combination.
`
`(emphasis added)That knowledge can not come from the applicant's invention itself.
`
`ATD Corporation v. Lydall, J11c. , 48 USPQ 2d 1321, 1329 (Fed. Cir. 1998)
`
`Determination of obviousness can not be based on the hindsight combination of components
`
`selectively culled from the prior art to fit the parameters of the patented invention. There must be a
`
`teaching or suggestion within the prior art, or within the general knowledge of a person of
`
`ordinary skill in the field of the invention, to look to particular sources of information, to select
`
`particular elements, and to combine them in the way they were combined by the inventor.
`
`(emphasis added)
`
`
`232 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`In Re: Fritch, 23 U.S.P.Q. 2d 1780 (Fed. Cir. 1992)
`
`-15-
`
`"Wilson and Hendrix fail to suggest any motivation for, or desirability of, the changes espoused by
`
`the Examiner and endorsed by the Board. Here, the Examiner relied upon hindsight to arrive at the
`
`detennination of obviousness. It is impermissible to use the claimed invention as an instruction
`
`manual or "template" to piece together the teachings of the prior art so that the claimed
`
`invention is rendered obvious (emphasis added). The court has previously stated that "( o ]ne cannot
`
`use hindsight reconstruction to pick and choose among isolated disclosures in the prior art to
`
`deprecate the claimed invention."
`
`Applicant's will now address the anticipation rejections by reviewing the alleged prior art documents
`
`and specifically what each of Olivieri, Hoffbrand (Ref. "U") or Hoffbrand (Ref. "V") teach.
`
`Referring to Olivieri, document U or document V, the Examiner respectively is advised that reaching
`
`general conclusions to support an alleged position of anticipation is insufficient when the overall
`
`teachings of the document are clear, and sadly lacking.
`
`Reference is now made to Olivieri, et al "Reduction of tissue iron stores and nonnalization of serum
`
`Jerri/in during treatment with the oral iron chelator deferiprone in thalassemia intennedia", 1992 in
`
`Blood, Vol. 79. The Examiner is not, respectfully, looking at the overall teachings thereof. The
`
`reference makes some general comments with regard to slight improvements over a nine month
`
`period in a patient with thalassem.ia intermedia, and on page 2744 at the bottom thereof, there is
`discussion that before Ll therapy there was an abnormal resting electrocardiogram and the various
`
`heart functions, and then after nine months ofLl therapy a comparison was made to those rates. It is
`
`stated that the abnormalities of the right ventricular dilatation and abnormalities in diastolic function
`
`did not change during Ll therapy except for a slight improvement in atrial contribution. This
`
`reference therefore suggests that it would be worthwhile to pursue, in spite of the complications
`inferred in the paper, the warranted use of Ll as a therapeutic option in patients with thalassemia
`
`intennedia having iron over-load. There is only discussion of mild improvement in the heart
`performance, but there is no discussion of the unexpected advantages pointed out in Applicant's
`
`disclosure that deferiprone is 4 times more effective than deferoxamine in managing cardiac
`
`problems in patients with thalassem.ia. Please note that the author of this reference in further study as
`
`supported in the prior discussion in, the reference from 1998 to Olivieri, et al changed her position
`with respect to the efficacy of deferiprone, in that it "May not provide adequate sustained control of
`
`body iron in a substantial proportion of Cooley's anemia patients."
`
`
`233 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-16-
`
`The question therefore remains, what therefore would be the state of the art; the submissions in 1992
`
`reference or those in the 1998 reference by the same leading author.
`
`Referring again to Olivieri it is clear that Olivieri particularly refers to a reduction in tissue iron
`
`stores and normalization of serum ferritin concentrations. The reference teaches that there was a
`dramatic improvement in signal intensity of the liver with respect to MRI results but only mild
`
`improvement for the heart. The report therefore provides "the first report of normalization of serum
`
`ferritin concentration in parallel with demonstrated reduction in tissue iron stores as a result of
`
`treatment with LI " . Clearly Olivieri refers to a reduction in tissue or body iron in serum ferritin
`
`levels and specifically the liver for only one individual and yet pointing to only mild improvement
`for the heart.
`
`Referring now to document "U" namely Hoffbrand, 1997, clearly the Examiner has read more into
`the teachings of Hofibrand than that which is present. The Examiner erroneously assumes that
`
`reducing body iron stores generally will reduce those in the heart. Hofibrand clearly states that
`
`deferiprone is capable of maintaining body iron stores at safe levels and that trials had been
`
`conducted to increase the dosages of deferiprone in order to achieve lower body iron burden in these
`
`patients. Clearly therefore Hoffbrand in 1997 did not appreciate the fact that deferiprone in fact
`would not necessarily decrease body iron burden in patients and even if it did there was no
`
`expectation that this might in fact relate to significant improvement in cardiac iron burden. In fact in
`
`document "U" Hoffbrand concludes that patients with cardiomyopathy due to iron overload should
`
`be given intravenous DFX rather than deferiprone. Hoffbrand therefore clearly points towards
`
`desferroxamine as opposed to deferiprone in the teachings of document "U" for patients experiencing
`cardiac problems.
`
`Referring now to document "V" also