Ex Parte Wald et alDownload PDFPatent Trial and Appeal BoardFeb 26, 201310257429 (P.T.A.B. Feb. 26, 2013) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte NICHOLAS J. WALD and MALCOLM R. LAW __________ Appeal 2011-006286 Application 10/257,429 Technology Center 1600 __________ Before TONI R. SCHEINER, DEMETRA J. MILLS, and JOHN G. NEW, Administrative Patent Judges. SCHEINER, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 14, 15, 21-24, 29, 34, 36-38, and 40, directed to a method for reducing the risk of cardiovascular disease. The claims have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. Appeal 2011-006286 Application 10/257,429 2 BACKGROUND According to the Specification, Under current clinical practice . . . , individuals found to have high values of the risk factors of cardiovascular disease are treated to reduce the risk factors (e.g. blood pressure or lipid level) to the so-called normal value, but no lower, by the application of one of many active principals known in the art. These high values may come to light as a result of routine health screening . . . . Alternatively an individual who has had the misfortune of suffering from a cardiovascular insult such as a heart attack or stroke, may receive treatment for one or more of the risk factors associated with cardiovascular disease. The proposition underlying this invention is that this policy and the practical clinical management of the policy is inefficient. (Spec. 2: 31- 3: 8.) The present inventors have demonstrated . . . that reducing the level of a risk factor below the accepted normal value gives rise to a concomitant reduction in the risk of cardiovascular disease. . . . Even within the population “normal” range, further reduction of the risk factor continues to provide further reduction in the risk of cardiovascular disease. By detailed analysis of the literature and the application of techniques of biomedical statistics and meta-analysis, the present inventors have shown that there is no effective lower threshold of the risk of cardiovascular disease in relation to the level of a particular risk factor . . . below which there is no further reduction in risk for further reductions in the risk factor. (Id. at 4: 26 - 5: 3.) [T]hus . . . there are considerable advantages in reducing the level of risk factors such as blood pressure, serum lipid levels, platelet function levels and serum homocysteine levels below the normal levels exhibited in a given population, even where none of these levels exceeds the normal level in an individual. (Id. at 5: 24-27.) Appeal 2011-006286 Application 10/257,429 3 The basis of the present invention is therefore that individuals should be treated irrespective of whether they exhibit particularly high[] values of any of the risk factors associated with cardiovascular disease or have a clinical history of cardiovascular disease, and that all risk factors should be changed. (Id. at 6: 1-5.) STATEMENT OF THE CASE Claims 14, 15, 21-24, 29, 34, 36-38, and 40 are pending and on appeal. Claims 1-13, 16-18, 19-20, 25-27, 30-33, 35, and 39 have been canceled (App. Br. 2). Claim 36 is representative: 36. A method for reducing the risk of cardiovascular disease comprising administering simultaneously, separately or sequentially to an individual with an unmeasured, or if measured normal blood pressure, active principals comprising at least two blood pressure lowering agents, each selected from a different physiological mode of action selected from a diuretic, a beta blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, and a calcium channel blocker, and at least one active principal from the following three categories: i) at least one lipid-regulating agent; ii) at least one serum homocysteine lowering agent; and iii) at least one platelet function altering agent. The Examiner relies on the following evidence: Posanski et al. US 4,794,111 Dec. 27, 1988 Nelson et al. US 5,663,186 Sep. 2, 1997 Tschollar et al. US 5,593,971 Jan. 14, 1997 Kristianson et al. US 5,686,451 Nov. 11, 1997 DeFelice US 5,962,020 Oct. 5, 1999 Appellants rely, in part, on the following additional evidence: Declaration of Professor Roderick J. Flower, submitted under 37 C.F.R. § 1.132, dated June 24, 2009 (“Flower Decl.”). Appeal 2011-006286 Application 10/257,429 4 Declaration of Dr. Malcom R. Law and Dr. Nicholas J. Wald, submitted under 37 C.F.R. § 1.132, dated July 31, 2007 (“Law & Wald Decl.”). Declaration of Dr. Frank E. Speizer, submitted under 37 C.F.R. § 1.132, dated May 26, 2009 (“Speizer Decl.”). Declaration of Dr. Jeffrey K. Aronson, submitted under 37 C.F.R. § 1.132, dated August 6, 2009 (“Aronson Decl.”). Linda Brooks, The Polypill - Coming Soon, http://www.medscape.com/viewarticle/471864 Natasha Rafter & Alistair Woodward, The ‘polypill’, friend or foe?, 28 AUSTRALIAN PRESCRIBER 82-83 (2005). Author(s) unknown, A strategy to reduce cardiovascular disease by more than 80%?, 17 WHO Drug Information (2003). FINDINGS OF FACT 1. Tschollar discloses a method of preventing the onset or reducing the risk of hypertension in a normotensive, insulin resistant subject by administering a cholesterol-lowering drug, alone or in combination with an angiotensin converting enzyme (ACE) inhibitor (Tschollar, col. 8, ll. 1-4). 2. According to Tschollar, suitable cholesterol-lowering drugs include HMG CoA reductase inhibitors and squaline synthetase inhibitors (Tschollar, col. 8, ll. 44-46), as well as “[o]ther cholesterol lowering drugs which function other than by inhibiting the enzyme HMG CoA reductase or squalene synthetase” (id. at col. 13, ll. 12-14), including aspirin (id. at col. 13, l. 30). Suitable ACE inhibitors include enalapril (id. at col. 14, l. 13). 3. According to Tschollar, “[h]yperinsulinemia appears to be the earliest and strongest detectable risk factor for coronary heart disease” in insulin resistant subjects (Tschollar, col. 1, ll. 43-45), and “[t]here is Appeal 2011-006286 Application 10/257,429 5 evidence that ACE-inhibition (ACEI) is able to positively influence insulin resistance” (id. at col. 2, ll. 16-17). 1 4. Tschollar teaches that the ACE inhibitor, “where employed, will preferably be administered in amounts below that required . . . to cause a reduction in blood pressure” (Tschollar, col. 8, ll. 35-38). 5. Kristianson discloses a composition “useful in the treatment of essential hypertension and congestive heart failure” (Kristianson, col. 2, ll. 37-39), comprising “an ACE inhibitor at the dose level normally employed in monotherapy . . . and a diuretic at a dose level which is the highest non- pharmacological dose” (id. at col. 2, ll. 8-13). 6. Roderick Flower, a Professor of Biochemical Pharmacology with over 40 years‟ experience of pharmacology and allied subjects, declares in relevant part: The patent by Tschollar et al specifically addresses a method for preventing or reducing the risk of hypertension in normotensive patients „with insulin resistance‟ (see „Field of Invention‟). My understanding, gained from reading the „Background‟ section, as well as from an examination of the literature quoted, is that . . . hypertension in this subset of patients is consequence of hyperinsulinaemia and insulin resistance. However, . . . these conditions are not the primary cause of hypertension in the general population[.] (Flower Decl. ¶ 2.) 1 Insulin resistance is “[w]hen the body‟s cells are resistant to the action of insulin,” while hyperinsulinemia refers to above normal insulin production by the pancreas as a result of insulin resistance. See e.g.: http://www.jewishhospitalcincinnati.com/cholesterol/research/insulin_resista nce.html Appeal 2011-006286 Application 10/257,429 6 7. Frank Speizer, a medical doctor and Professor of Medicine with expertise as a chronic disease epidemiologist involved in large scale population based studies and as a pulmonary physician treating patients with a variety of cardiopulmonary diseases, declares in relevant part: Prior to April 2000, efforts to reduce the risk of cardiovascular disease had been based on clinicians treating individual patients on the basis of guidelines related to individual signs and symptoms or laboratory measures reflecting abnormal levels for a specific condition. (Speizer Decl. ¶ 4.) The present application reveals the benefit of intervening on several causal risk factors simultaneously, regardless of the presence of the individual risk factor in a given individual. This proposal represents a significant departure from accepted practice in April 2000 as well as up to the present time. Most medical practitioners, even today, as well as certainly prior to April 2000 would not have considered any need to prescribe to a patient a blood pressure lowering drug (even one let alone two or more as indicated in the patent application) if that patient did not have elevated blood pressure. (Id. at ¶ 6.) 8. Dr. Jeffrey Aronson, a medical doctor specializing in General (Internal) Medicine, and a consultant clinical pharmacologist, declares in relevant part: Before April 2000 attempts to reduce the risks of cardiovascular disease were directed at identifying so-called high-risk patients, in other words those with a factor or factors that increase their risk of cardiovascular disease. This is still mostly the case today. Such risk factors include a raised blood pressure and a raised serum cholesterol. (Aronson Decl. ¶ 6.) Appeal 2011-006286 Application 10/257,429 7 Those in whom such factors are identified, or are assumed to be present from other clinical evidence, are offered treatment, usually with drugs, with the aim of correcting the abnormal factors and thus reducing the risks of cardiovascular disease. However, it was not the practice, and is still not commonly so, to offer treatment to modify such risk factors in low-risk patients or to attempt to modify factors such as blood pressure or serum cholesterol in those in whom the values of those variables are considered to be normal. . . . This contrasts markedly with the method described in the application concentration. (Id. at ¶ 7.) 9. According to Linda Brooks, “[a]lthough the initial publication [of the present inventors‟ „polypill‟ idea] was met with a degree of skepticism, it appears that the concept was prescient and that over the next 10 years many different versions of the polypill will become available” (Brooks 1). 10. According to Natasha Rafter and Alistair Woodward: In June 2003 the British Medical Journal (BMJ) published a paper [by Wald and Law, the present inventors] which claimed that taking a daily pill containing six active ingredients would prevent more than 80% of cardiovascular events. The proposed „polypill‟ contains aspirin, a „statin‟, three blood pressure lowering agents (a thiazide, a beta blocker and an ACE inhibitor) and folic acid. Few papers have provoked such debate and raised tempers so high. (Rafter 82, col. 1 (internal citations omitted).) It is generally accepted that patients with previous cardiovascular disease require treatment with antiplatelet, blood pressure lowering and cholesterol lowering therapies. Where the controversy lies is the concept of a fixed dose, and widespread use of the polypill in primary prevention. . . . Mass medication can be justified from a population perspective when Appeal 2011-006286 Application 10/257,429 8 the burden of disease is high, but it is difficult to defend at an individual level in those at low risk. (Id. (internal citations omitted).) 11. An article (authors unknown) published under the aegis of the World Health Organization describes preventive administration of a formulation comprising a statin, e.g. simvastatin; three blood pressure lowering drugs, e.g., a thiazide, a beta blocker, and an ACE inhibitor; folic acid, and aspirin as “radical” (WHO Drug Information). DISCUSSION The Examiner has rejected claims 14, 15, 21-24, 34, 36-38, and 40 under 35 U.S.C. § 103(a) as unpatentable over Tschollar and Kristianson. The Examiner has also rejected claim 29 as unpatentable over Tschollar, Kristianson, Posanski, Nelson, and DeFelice. Since the same issue is dispositive for both rejections, we will consider them together. Representative independent claim 36 is directed, in relevant part, to a method for reducing the risk of cardiovascular disease of an individual with an unmeasured, or if measured normal blood pressure, by administering at least two blood pressure lowering agents with different physiological modes of action and at least one agent selected from the following three categories: a lipid-regulating agent; a serum homocysteine lowering agent; and a platelet function altering agent. In response to a requirement for an election of species, Appellants elected enalapril (an ACE inhibitor) and hydrochlorothiazide (a diuretic) as the two blood pressure lowering agents; simvastatin as the lipid-regulating agent; folic acid as the serum homocysteine lowering agent; and aspirin as the platelet function altering agent (Appellants‟ Response, submitted June Appeal 2011-006286 Application 10/257,429 9 15, 2006). Our understanding is that the application has been examined only with respect to combinations of these particular agents. The Examiner finds that Tschollar discloses a method of preventing or reducing the risk of hypertension in normotensive patients by administering an ACE inhibitor, e.g., enalapril, in combination with a cholesterol lowering agent, e.g., aspirin (Ans. 4). The Examiner acknowledges that Tschollar “fails to teach the elected second blood pressure lowering agent, hydrochlorothiazide” (id. at 5), but finds that Kristianson “teaches a composition comprising an angiotensin converting enzyme (ACE) inhibitor enalapril and a diuretic hydrochlorothiazide used in treating hypertension and disorders associated therewith such as congestive heart failure” (id.). The Examiner concludes that it would have been obvious for one of ordinary skill in the art to administer hydrochlorothiazide, enalapril, and aspirin to Tschollar‟s normotensive patients because “it was well known in the art that all components demonstrate efficacy in treating the same disease or disorder hypertension” (id. at 6), and “[i]t is prima facie obvious to use in combination two or more agents that have previously been used separately for the same purpose” (id.). Appellants contend, in part, that Tschollar‟s normotensive patients are also insulin resistant, and their insulin resistance and accompanying hyperinsulinemia is an underlying risk factor for hypertension (App. Br. 12), and that Tschollar administers a cholesterol lowering drug, and an ACE inhibitor in order to prevent hypertension by treating the underlying cause (id.). Appellants contend that Kristianson, on the other hand, uses an ACE inhibitor and a diuretic to treat existing hypertension (id. at 15), and Appeal 2011-006286 Application 10/257,429 10 “provides no suggestion to . . . apply the disclosed method to individuals who have a normal or an unknown blood pressure” (id.). The issue raised by the present rejections is whether the Examiner has established that it would have been obvious for one of ordinary skill in the art to administer hydrochlorothiazide, in addition to enalapril and aspirin, to normotensive subjects, given the evidence of record. Having considered all of the evidence of record, we agree with Appellants that the claimed invention would not have been obvious over the combined teachings of Tschollar and Kristianson. While the claims are directed to a method of treating normotensive subjects in general, and “the method described [by] Tschollar is applied only to the narrow population consisting of normotensive patients that are insulin resistant” (App. Br. 12), the Examiner is correct that “the claims do not exclude the patients taught by Tschollar” simply by being broader (Ans. 11). However, the insulin resistant status of Tschollar‟s subjects is relevant when considering the Examiner‟s proposed combination of Kristianson with Tschollar. Tschollar‟s focus is on preventing hypertension in normotensive, insulin resistant subjects. According to Dr. Roderick Flower, hypertension develops in these subjects as “[a] consequence of hyperinsulinemia and insulin resistance . . . [which] are not the primary cause of hypertension in the general population” (Flower Decl. ¶ 2; FF6). Moreover, Tschollar teaches that an ACE inhibitor, when included as an adjunct to the cholesterol lowering drug, should be “administered in amounts below that required . . . to cause a reduction in blood pressure” (Tschollar, col. 8, ll. 35-38; FF4). Appeal 2011-006286 Application 10/257,429 11 Kristianson, on the other hand, administers hydrochlorothiazide (a diuretic) and enalapril to treat existing hypertension (FF5). We disagree with the Examiner that this fact would have led one of ordinary skill in the art to administer hydrochlorothiazide to Tschollar‟s normotensive subjects, in addition to an ACE inhibitor and a cholesterol lowering drug. Tschollar administers enalapril and aspirin for their purported beneficial effects on insulin resistance and cholesterol levels, respectively. That is, Tschollar‟s focus is on preventing hypertension in normotensive patients by treating conditions attendant on insulin resistance (hyperinsulinemia and high cholesterol levels) (FFs 3, 4, 6). However, the Examiner has not established that hydrochlorothiazide was known to have any effect on insulin resistance, hyperinsulinemia, or cholesterol levels. Thus, the Examiner has not established that Tschollar and Kristianson use the three agents “separately for the same purpose” (Ans. 6). Even if we were to accept the Examiner‟s assertion that hydrochlorothiazide, enalapril, and aspirin are separately known for treating hypertension, at best that would suggest administering all three to a hypertensive subject, rather than to Tschollar‟s normotensive subjects. Moreover, we note that the Examiner‟s erroneous characterization of Professor Flower‟s declaration as merely expressing “an opinion” (id. at 14), and the Examiner‟s summary dismissal of the declaration without discussing any of Professor Flower‟s factual assertions, much less presenting evidence to the contrary, is improper. Even “[o]pinion testimony rendered by experts must be given consideration, and while not controlling, generally is entitled to some weight.” Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985). Appeal 2011-006286 Application 10/257,429 12 Finally, there is considerable evidence of record that administering two blood pressure lowering agents, with different mechanisms of action, to a subject without measured hypertension would have represented a substantial departure from accepted practice, and that the concept was met with considerable skepticism when introduced. Merely by way of example, we note the declarations of Drs. Speizer and Aronson, wherein both declarants indicate that administering the drugs in question to normotensive subjects would have run contrary to accepted practice at the time of the invention (FFs 7, 8). The Examiner has not questioned the qualifications of the Declarants as persons of skill in this art, and their statements are not merely unsupported opinions - they are objective evaluations of what was (and was not) accepted practice in the art at the time of the invention. It is well settled that proceeding contrary to the accepted wisdom in the art is strong evidence of unobviousness. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 1552 (Fed. Cir. 1983). In addition, there is considerable anecdotal evidence of record that others of skill in the art initially regarded Appellants‟ invention with skepticism (see e.g., articles by Brooks (FF9), Rafter (FF10), and the 2003 WHO Drug Information article (FF11)). The Examiner has not addressed any of this evidence in a meaningful way - indeed the Examiner merely states that “the Speizer and Aronson Declarations of record have been considered” (id. at 14), but does not comment on the substance of either Declaration, and summarily dismisses “[t]he letters and articles submitted by Appellant” as subjective opinions (Ans. 13). Again, the Examiner‟s treatment of the evidence relied on by Appellants is improper. Appeal 2011-006286 Application 10/257,429 13 CONCLUSION The Examiner has not established that it would have been obvious for one of ordinary skill in the art to administer hydrochlorothiazide, in addition to enalapril and aspirin, to normotensive subjects, given the evidence of record. SUMMARY We reverse the rejection of claims 14, 15, 21-24, 34, 36-38, and 40 as unpatentable over Tschollar and Kristianson, as well as the rejection of claim 29 as unpatentable over Tschollar, Kristianson, Posanski, Nelson, and DeFelice with respect to the elected species. REVERSED cdc Copy with citationCopy as parenthetical citation