Bone Care International, LLC v. Pentech Pharmaceuticals, Inc. (862 F. Supp. 2d 790, 2012)

United States District Court for the Northern District of Illinois 2012-03-22

Citations

Full opinion text

MEMORANDUM OPINION AND ORDER INCORPORATING FINDINGS OF FACT AND CONCLUSIONS OF LAW FOLLOWING BENCH TRIAL

ROBERT M. DOW, JR., District Judge.

This patent infringement case concerns Plaintiffs Bone Care International’s and Genzyme Corporation’s (“Plaintiffs”) patented pharmaceutical drug, Hectorol®, of which Defendants Pentech Pharmaceuticals, Inc., and Cobrek Pharmaceuticals, Inc., (“Defendants”) seek to produce and sell a generic version. The Court presided over a lengthy bench trial in October and November 2010 on the issues of the validity and enforceability of Plaintiffs patent for Hectorol®. Having carefully considered the evidence presented at trial as well as the parties’ lengthy post-trial submissions and applied that evidence against the pertinent legal standards, the Court concludes that the patent is both valid and enforceable. Specifically, the Court holds as follows:

(1) As the parties stipulated prior to trial, Defendants have infringed claim 7 of the '116 patent (see Trial Tr. 16:4-17:18; 17:25-18:10);

(2) Notwithstanding the absence of any express finding by the patent examiner, Plaintiffs are entitled to a 1988 priority date because Example 4 of the '371 application satisfies the written description and enablement criteria;

(3) Even with the Perry article and other recent publications, Defendants have not come forward with sufficiently strong evidence from which the Court could conclude that the invention claimed by Plaintiffs is inoperable;

(4) Although Plaintiffs’ invention was a good candidate for further study as of 1988, Defendants have not shown that it was either obvious or obvious to try as of that date;

(5) Because Plaintiffs are entitled to the 1988 priority date, the references that Dr. Bishop allegedly failed to disclose to the PTO, all of which post-dated the priority date, are immaterial as a matter of law, and Bishop therefore did not engage in inequitable conduct.

In the opinion that follows, the Court sets out its findings of fact and conclusions of law pursuant to Fed.R.Civ.P. 52(a). In the interest of readability, the Court has integrated its findings of fact and conclusions of law into a single analysis section. The Court has endeavored to indicate with citations to the record the testimony and other evidence on which it has relied in making findings of fact and has noted those instances in which its findings have been influenced by credibility determinations.

I. Background

A. Factual Background

Hectorol® is an injectable drug indicated for the treatment of patients with hyperparathyroidism secondary to (“SHPT”) end-stage renal disease (“ESRD”). [616, at ¶ 434.] Its active ingredient is a vitamin D2 compound called doxercalciferol (also referred to by its chemical abbreviation, laOHD2, or one-alpha-hydroxy-vitamin D2 )•

Hectorol® is covered by claim 7 of the patent-in-suit, U.S. Patent 5,602,116 (“the '116 patent”), entitled “Method for Treating and Preventing Secondary Hyperparathyroidism.” Claim 7 teaches a method of using an effective amount of doxercalciferol to lower and maintain lowered parathyroid hormone (“PTH”) levels in human patients who suffer from hyperparathyroidism (“HPT” or “SHPT”) secondary to end-stage renal disease (“ESRD”). The '116 patent issued on February 11, 1997, from the '488 application, which was filed on April 3, 1995. The '116 patent is related, through a chain of continuation and continuation-in-part patent applications, to the '371 application (also known as the “parent application”), which was filed on August 2, 1988. (Sofocleous Trial Tr. 1351:16-1352:12, citing DTX 1262.) The '116 patent was issued to inventors Joyce Knutson, Ph.D., Charles Bishop, Ph.D., and Richard Mazess, Ph.D., and was assigned to Bone Care. The '116 patent expires on February 11, 2014. [616, at ¶ 435.] On April 6, 2000, the U.S. Food and Drug Administration (“FDA”) approved Plaintiff Genzyme’s New Drug Application (“NDA”) for doxercalciferol, and Plaintiffs began producing and selling the drug under the brand name Hectorol®. [616, at ¶¶ 430-33.]

Defendants Pentech Pharmaceuticals, Inc., and Cobrek Pharmaceuticals, Inc. (“Defendants”) filed an Abbreviated New Drug Application (“ANDA”) with the U.S. Food and Drug Administration (“FDA”) that sought the FDA’s approval to manufacture, produce, and market a generic version of Hectorol®. Plaintiffs subsequently brought this lawsuit against Defendants under the Hatch-Waxman Act, 35 U.S.C. § 271(e)(2), alleging that, as a result of the filing of the ANDA, Defendants were liable for infringement of claim 7 of the '116 patent. Plaintiffs seek a declaratory judgment, injunctive relief, litigation costs, attorneys’ fees, and — in the event that Defendants proceed with the manufacture, use, or sale of doxercalciferol prior to the 2014 expiration of the '116 patent— money damages. [197.] Defendants answered and counterclaimed that claim 7 of the '116 patent is invalid and unenforceable under various theories. [227.] Specifically, Defendants counterclaimed that (1) claim 7 was obvious in view of the prior art, (2) the '116 patent is not entitled to a priority date earlier than April 3,1995, and thus, that any art prior to that date may be considered by the Court in its assessment of obviousness, and (3) the '116 patent is unenforceable because Plaintiffs’ inventors and patent attorneys committed inequitable conduct in prosecuting the patent applications before the U.S. Patent and Trademark Office (“PTO”) that ultimately led to issuance of the '116 patent. Defendants also contend that the '116 patent is inoperable. Defendants seek attorneys’ fees based on the alleged inequitable conduct.

B. Plaintiffs’ Motion to Dismiss Defendants’ Counterclaims A, B, C, D, E, F, G, and IX

Plaintiffs moved to dismiss Defendants’ inequitable conduct affirmative defenses and counterclaims A-G. [241]. The Court granted in part and denied in part Plaintiffs’ motion, dismissing Defendants’ affirmative defenses and counterclaims A, B, C, and E, but denying the motion as to affirmative defenses and counterclaims D, F, and G. [327]

Defendants alleged in affirmative defense and counterclaim D that Plaintiffs engaged in inequitable conduct in prosecuting the '488 application — a continuation-in-part application that eventually issued as the '116 patent — by intentionally failing to submit to the PTO material prior art references that had been disclosed during prosecution of the '488 application’s ancestor applications. Defendants alleged in counterclaim and affirmative defense F that Plaintiffs engaged in inequitable conduct in filing the '488 application because they intentionally failed to disclose to the PTO abstracts and posters (“the Gallagher Abstracts”) that were material to the '488 application and antedated its 1995 filing date. In counterclaim and affirmative defense G, Defendants alleged that claim 7 of the '116 is unenforceable because Plaintiffs engaged in inequitable conduct when they submitted to the PTO a 1994 article coauthored by one of the inventors of claim 7 despite knowing that the article obscured the existence of the Gallagher Abstracts.

C. Claim Construction

After holding a tutorial and claim construction hearing and considering the parties’ claim construction briefs, the Court construed claim 7 as follows:

A method for lowering elevated blood concentrations of parathyroid hormone (“PTH”) or maintaining lowered blood concentrations of PTH in human patients having increased above normal) secretion of PTH by the parathyroid gland as a result of a disease wherein the patients’ kidneys no longer function at a level necessary to sustain life and thus require chronic dialysis or kidney transplantation, comprising: administering an amount of la-OH-vitamin D2 sufficient to lower and maintain lowered blood concentrations of PTH with a lower incidence of hypercalcemia than would result from using la,25(OH)2 vitamin D3 or la-OH vitamin D3 to achieve the same level of PTH suppression.

[468.] In other words, claim 7 requires that at a dose that is equipotent to, or equivalently effective as, calcitriol (la,25(OH)2 vitamin D3) and alfaealcidol (la-OH vitamin D3) — that is, a dose that produces the same level of PTH suppression as the other two compounds — doxercalciferol (la-OH-vitamin D2) would achieve a lower incidence of hypercalcemia.

D. Plaintiffs’ Motions for Summary Judgment on Defendant’s Counterclaims D, F, G, and IX

Plaintiffs moved for summary judgment on counterclaim and affirmative defense D. [332.] Plaintiffs argued that there were no genuine issues of material fact regarding whether Plaintiffs satisfied their duty to disclose the prior art references to the PTO during prosecution of the '488 application, as Plaintiffs had disclosed the relevant prior art references in the ancestor applications and bore no additional duty to re-submit the references. Plaintiffs argued that Defendants had not sufficiently rebutted the presumption that the PTO examiner had reviewed the ancestor applications during prosecution of the '488 application in compliance with governing PTO guidance. The Court agreed, and granted Plaintiffs’ motion for summary judgment motion on counterclaim D. [496, 528.]

Plaintiffs also moved for summary judgment on inequitable conduct counterclaims and affirmative defenses F and G, as well as counterclaim IX. [336.] In counterclaim IX, Defendants seek attorneys’ fees pursuant to 35 U.S.C. § 285 on the ground that Plaintiffs engaged in litigation misconduct by arguing that claim 7 of the '116 patent is entitled to a 1988 priority filing date. The Court denied Plaintiffs motion for summary judgment with respect to affirmative defenses and counterclaims F, G, and counterclaim IX. [498.]

E. Trial

The Court held a bench trial in October and November 2010. At trial, Defendants challenged the '116 patent on three grounds. First, Defendants argued that claim 7 was invalid because it was entitled only to its 1995 priority date (the date on which the '116 patent issued) rather than the August 2,1988 priority date of the '371 parent application. Specifically, Defendants contended that claim 7 did not meet the 35 U.S.C. § 120 priority date requirements of enablement and written description, as set forth in 35 U.S.C. § 112, ¶ 1. Second (and related to the first), Defendants argued that claim 7 was invalid because it was obvious from prior art, assuming that it was entitled only to the 1995 priority date, under 35 U.S.C. § 103. Third, Defendants argued that the '116 patent is unenforceable based on inequitable conduct. Defendants also seek attorneys’ fees under 35 U.S.C. § 285.

1. Expert Testimony

a. Plaintiffs’ Experts

Plaintiffs’ expert Dr. Craig B. Langman is a nephrologist who treats ESRD patients, SHPT patients, and metabolic bone disease patients with doxercalciferol and calcitriol. (Langman Trial Tr. 1760:4-17, 1760:23-1761:2, 1761:3-11, 1762:18-22.) Dr. Langman has been an investigator in many clinical trials, including some relating to vitamin D studies in ESRD patients, and teaches a course on clinical trial design. (Langman Trial Tr. 1761:12-18, 1762:17-24.) Dr. Langman testified at trial about what the '116 patent’s ancestor application — the '371 application — would have conveyed to a person of ordinary skill in the art (“POSA”) at the time of its filing in 1988. (Langman Trial Tr. 1759:22-1761:11; Keana Trial Tr. 556:24-557:19; Segre Trial Tr. 658:10-17; Segre Deposition Tr. 39:2-7.)

Plaintiffs expert Dr. Anthony Norman has a Ph.D. in biochemistry and conducted his doctoral research in the laboratory of Dr. Hector DeLuca (the inventor of doxercalciferol), where he studied the synthesis of vitamins D2 and D3. (Norman Trial Tr. 2107:9-23.) Dr. Norman’s subsequent research and publications have all focused on vitamin D research. (Norman Trial Tr. 2109:14-2110:18, 2113:6-2114:18.)

Plaintiffs’ expert Mr. Richard A. Kill-worth is a patent attorney who has worked at the PTO, the U.S. Court of Customs and Patent Appeals, and in private patent law practice.

b. Defendants’ Experts

Defendants’ expert Dr. Leonard J. Deftos is a board-certified endocrinologist and internist who works in the field of bone and calcium metabolism. Dr. Deftos manages the treatment of patients with SHPT, and manages and directs clinical and research laboratories assessing patients with calcium and bone disease by measuring PTH levels and vitamin D. Dr. Deftos has published extensively on vitamin D with respect to bone and calcium metabolism. Dr. Deftos also has J.D. and L.L.M. law degrees.

Defendant’s expert Dr. John F.W. Keana is a Ph.D. and expert in synthetic and medicinal chemistry. Dr. Keana is the inventor or co-inventor of numerous patents in the area of medicinal chemistry, and has extensive experience prosecuting pharmaceutical patents and consulting for and managing pharmaceutical companies.

Defendants’ expert Dr. Gino V. Segre is a medical doctor and board-certified internist. His work focuses on the diagnosis and treatment of patients with disordered calcium metabolism and bone-loss — especially parathyroid gland diseases and renal disease. Dr. Segre has published numerous papers on PTH metabolism, chronic kidney disease, and vitamin D.

Defendants’ expert Mr. Michael Sofocleous is a patent lawyer with experience in private patent litigation and in the prosecution of patents within the PTO. He spent more than 30 years working as a PTO examiner, a patent interference examiner for the Board of Patent Interferences, and an administrative patent judge at the Board of Patent Appeals and Interferences.

2. Fact Witnesses

a. Plaintiffs’ Fact Witnesses

Plaintiffs called as a fact witness Dr. Charles W. Bishop, Ph.D., one of the named inventors on and co-authors of the '116 patent and its ancestor applications. Dr. Hector DeLuca, the creator of doxercalciferol, appeared via video.

b. Defendants’ Fact Witnesses

Defendants called as a fact witness Dr. Donald J. Sherrard, a medical doctor with clinical and research experience treating ESRD patients with vitamin D analogs.

II. Analysis

Where, as here, the PTO has issued a patent, that patent is entitled to a presumption of validity and enforceability. 35 U.S.C. § 282. A party seeking to show that the patent is invalid or unenforceable must do so by clear and convincing evidence. Research Corp. Techs. v. Microsoft Corp., 627 F.3d 859, 870-71 (Fed.Cir.2010). Thus, for example, if a patent challenger seeks to show that a patent is invalid due to prior art, the challenger must provide clear and convincing evidence that the pri- or art is invalidating. Id.; Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327, 1329 (Fed.Cir.2008). Here, Defendants’ “burden to prove invalidity” — an “ultimate burden[] of persuasion” — never “shifts to the other party.” Tech. Licensing Corp., 545 F.3d at 1327. Rather, “the risk of decisional uncertainty stays on the proponent of the proposition.” Id.

A. Person of Ordinary Skill in the Art

The trier of fact must determine whether a patent can claim priority under 35 U.S.C. § 120 (i.e., is enabled and provides sufficient written description under 35 U.S.C. § 112, ¶ 1) or is obvious under 35 U.S.C. § 103 from the perspective of a person of ordinary skill in the art (“POSA”) as of the claimed priority filing date. A POSA is a hypothetical person. (Langman Trial Tr. 1770:12-1771:2.) The parties contest how the Court should define a POSA for purposes of this case.

Plaintiffs’ experts testified that the POSA has either a medical degree and is board-certified in nephrology or endocrinology or a Ph.D. in biochemistry and at least two years of experience in the field of vitamin D drug discovery. (Langman Trial Tr. 1770:22-1771:2; Norman Trial Tr. 2121:23-2125:11.) Defendants’ experts testified that the POSA has both a medical degree with a specialization in nephrology or endocrinology and clinical experience treating ESRD and “significant experience” in vitamin D and parathyroid research. (Deftos Trial Tr. 42:14-21; Segre Trial Tr. 672:11-19.) Defendants state that “significant experience” could be a Ph.D. in biochemistry or a related field or research experience equivalent to that of a Ph.D. Neither Defendants nor Plaintiffs presented as expert witnesses any individual who has both a medical degree and a Ph.D. or equivalent research experience in the relevant fields. Moreover, the inventors of the '116 patent were Ph.D.s, but none was a medical doctor.

The Court concludes that for purposes of this case, the POSA is an individual who has either a medical degree and is board-certified in nephrology or endocrinology or a Ph.D. in biochemistry and at least two years of vitamin D research experience. As indicated by the fact that both parties called as experts individuals who held one or the other (but not both) of these qualifications, the Court believes that either combination of educational and professional background is sufficient to qualify someone as a person with ordinary skill in the art of treating ESRD and SHPT patients with vitamin D drugs. For example, a board-certified nephrologist or endocrinologist physician would have ordinary skill in identifying, from a clinical perspective, which treatment among the range of known and available treatments would be most appropriate for this patient group; a Ph.D doctorate would have ordinary skill in identifying, from a biochemical research perspective, the same from a laboratory environment.

B. Infringement

Prior to trial, Defendants stipulated to infringement of claim 7 of the '116 patent. Accordingly, the Court need not further discuss any issues relating to infringement.

C. Priority

Bone Care filed the '488 application— which eventually issued as the '116 patent-in-suit — on April 3,1995, as a continuation-in-part application of the '371 application. Through claim 7 of the '116 patent, Plaintiffs claim priority to the August 2, 1988 filing date of the '371 application pursuant to 35 U.S.C. § 120. [616, at ¶213 (citing Sofocleous Trial Tr. 1356:3-1357:10).] Defendants have mounted a challenge to Plaintiffs’ claim to the priority filing date of August 2, 1988, asserting that claim 7 is entitled only to the April 3,1995 filing date of the '488 application. In sorting out the priority issue, the Court must navigate a fairly complex web of standards, burdens, and terminology — all of which is made more challenging by the absence of any express finding on priority by the patent examiner in this case.

1. The '371 Application

Plaintiffs filed the '371 application on August 2, 1988. [616, at ¶ 207 (citing Kill-worth Trial Tr .2045:18-2045:20).] Dr. Bishop drafted the '371 application along with Carl Gulbrandsen, Bone Care’s patent attorney. [616, at ¶ 243 (citing Bishop Trial Tr. 1564:15-18).] Dr. Bishop wrote all four examples in the '371 application. [610, at ¶ 245 (citing Bishop Trial Tr. 1565:18-21; 1566:15-16; 1566:24-1567:4; 1615:12-16).]

The '371 application contains four examples: Example 1 reports H-101, an actual human clinical trial of doxercaleiferol in six post-menopausal osteoporotic women. [616, at ¶ 209 (citing Langman Trial Tr. 1775:11-1775:17).] Examples 2 and 3 are prophetic examples — that is, they describe clinical trials that had not yet been conducted at the time of filing — of clinical trials in which doxercaleiferol was administered to treat osteoporosis in women. [616, at ¶ 210 (Langman Trial Tr. 1776:2-1776:6).] Bone Care’s H-102 protocol, which it submitted to the FDA in May 1989, was written in accordance with example 2 of the '371 patent. [616, at ¶ 254 (citing Bishop Trial Tr. 1567:7-11,1569:14-1570:9).] Bone Care’s H-103 and H-104 protocols, which were submitted to the FDA in April 1991, were written in accordance with example 3. [616, at ¶ 255 (citing Bishop Trial Tr. 1567:7-14, 1570:10-1571:16).]

Like examples 2 and 3, example 4 of the '371 application is a prophetic example. [616, at ¶ 247 (citing Bishop Trial Tr. 1565:9-21, 1566:20-1567:9).] Example 4 describes a clinical trial in which doxercalciferol is administered as a treatment for patients with renal disease. [616, at ¶ 211 (citing Langman Trial Tr. 1776:18-1776:22) ]. Example 4 of the '371 application describes a randomized, double-blind placebo-controlled study of 30 men and women who have renal disease and are undergoing chronic hemodialysis. [616, at ¶ 216, 224 (citing Langman .Trial Tr. 1778:13-16, 1782:21-1784:22).] Example 4 divides the 30 patients into two groups, one of which receives doxerealeiferol (the treated group) while the other receives a placebo (the untreated group). [616, at ¶ 220 (citing Bishop Trial Tr. 1604:10-19; Langman Trial Tr. 1776:2-22; Keana Trial Tr. 376:3-21).] Both groups of patients undergo an eight-week control period during which the patients’ prior renal disease therapy — including any vitamin D therapy — is stopped, so as not to influence the results of the trial. [616, at ¶ 221 (citing Langman Trial Tr. 1781:22-1782:15, Segre Trial Tr. 959:6-23, Keana Trial Tr. 376:3-21).] The primary endpoint for measuring results in Example 4 was a measurement of serum calcium. [610, at ¶ 69 (citing Keana Trial Tr. 372:7-374:14, 377:7-11, 377:22-378:10, 380:2-18, 390:9-12; Segre Trial Tr. 932:1-5, 936:22-937:5; Bishop Deposition Tr. 157:14-20).]

Example 4 reported results of the placebo group of patients showing frequent hypocalcemia as well as significant reductions in radial and spinal bone density. [616, at ¶ 226 (citing Langman Trial Tr. 1785:8-11, Langman 1790:13-1792:6).] The example describes the treated group of patients as reporting results of normalized serum calcium levels and stable radial and spinal bone densities. [616, at ¶234 (Langman Trial Tr. 1797:1-10).] The treated patient group is reported to have an “insignificant” incidence of hypercalcemia. [616, at ¶ 238 (citing Langman Trial Tr. 1801:5-8).] Bone Care submitted the H-106 protocol to the FDA in September 1994. The protocol was written in accordance with example 4 and sought the FDA’s approval for using doxerealeiferol to treat patients with ESRD and SHPT. [616, at ¶ 256 (citing Bishop Trial Tr. 1567:14-17, 1571:7-1573:3).] When the H-106 protocol was approved — after the '488 application was filed — Bone Care conducted the first human clinical trial of doxerealeiferol on ESRD and SHPT patients. [610, at ¶ 8 (citing Bishop Trial Tr. 1571:10-1572:2).]

The '371 application states that the four examples included in the application “demonstrate that [doxerealeiferol] is effective in preventing or restoring the loss of bone mineral content while being substantially less toxic than [alfacalcidol].” [616, at ¶ 240 (citing Langman Trial Tr. 1801:9-15).]

2. Claim 7 of the '116 Patent

Bone Care filed the '488 application— which ultimately issued as the '116 patent — on April 3, 1995. [616, at ¶ 267 (citing Sofocleous Trial Tr. 1351:16-1352:12; Bishop Trial Tr. 1612:2-11).] The '488 application was filed as a continuation-in-part application of earlier patent applications that ultimately led back to the '371 “parent” application. [615, at ¶ 267.] At the time of filing of the '488 application, doxercalciferol had been administered to treat osteoporosis in women, but had not been administered as a treatment for men and women diagnosed with SHPT and ESRD. [610, at ¶ 8 (citing Bishop Trial Tr. 1571:10-1572:2).]

While the claims of the '371 application were directed in large part to the treatment of osteoporosis patients, the claims of the '488 application were directed to the treatment of ESRD and SHPT patients. [616, at ¶ 267 (citing Sofocleous Trial Tr. 1351:16-1352:12; Bishop 1612:2-11).] Specifically, claim 7 of the '116 patent teaches a method of administering doxercalciferol to ESRD and SHPT patients. [616, at ¶ 274 (citing Bishop Trial Tr. 1615:20-24).] The endpoint described in claim 7 is the measurement of PTH. [616, at ¶ 270.] As construed by the Court, claim 7 describes:

A method for lowering elevated blood concentrations of parathyroid hormone (“PTH”) or maintaining lowered blood concentrations of PTH in human patients having increased (i.e., above normal) secretion of PTH by the parathyroid gland as a result of a disease wherein the patients’ kidneys no longer function at a level necessary to sustain life and thus require chronic dialysis or kidney transplantation, comprising: administering an amount of Ta-OH-vitamin D2 sufficient to lower and maintain lowered blood concentrations of PTH with a lower incidence of hypercalcemia than would result from using let,25(OH)2 vitamin D3 or la-OH vitamin D3 to achieve the same level of PTH suppression.

[468.] As construed, claim 7 may be broken down into four “key elements”:

1) human patients suffering from ESRD;

2) SHPT;

3) lowering and maintaining lowered PTH levels;

4) with a lower incidence of hypercalcemia.

[616, at ¶ 212.]

3. The PTO Examiner’s Determination of Priority During Prosecution of the '116 Patent

Before turning to whether, in the Court’s view, example 4 of .the '371 application would reasonably have conveyed to a POSA as of 1988 the invention set forth in claim 7 of the '116 patent, the Court will address the parties’ contentions concerning whether the PTO examiner expressed any view on that subject. For, if he did so explicitly, the examiner’s views would require the Court to place a thumb on the scale in favor of Plaintiffs on the issue of priority. But if that is not so, then the Court must make an independent assessment, applying the standards set forth under controlling Federal Circuit law.

The PTO issued the '116 patent on February 11, 1997. The '116 patent issued from a chain of five patent applications:

1. Application no. 415,488 (“ '488 application”), filed on April 3,1995 and issued as the '116 patent on February 11, 1997;

2. Application no. 119,895 (“ '895 application”), filed on September 10, 1993 and issued as U.S. Patent No. 5,403,831 (“ '831 patent”) on April 4,1995;

3. Application no. 812,056 (“ '056 application”), filed on December 17, 1991;

4. Application no. 569,412 (“ '412 application”), filed on August 17, 1990 and issued as U.S. Patent No. 5,104,864 (“ '864 patent”) on April 14, 1992; and 5. Application no. 227,371 (“ '371 patent application”), filed on August 2, 1988.

[616, at ¶ 275 (Sofocleous Trial Tr. 1351:11-1352:12).]

When it was first filed, the '488 application did not specifically reference the '371 application in its relate-back clause. [616, at ¶ 277 (Killworth Trial Tr .2047:8-2047:13).] The '488 application initially included 16 claims, which were directed to methods of treatment, compositions, pharmaceutical compositions, and an article of manufacture. [616, ¶ 278 (citing joint trial exhibits).] In a Preliminary Amendment dated April 29, 1996, Plaintiffs added four new claims: claims 17-20. [616, at ¶ 279.] Claim 17 of the '488 application ultimately issued as claim 7 of the '116 patent. [616, at ¶ 280 (Killworth Trial Tr.2046:13-2046:18, 2047:22-2048:7).]

PTO Examiner Criares (“the Examiner”) held an interview with Plaintiffs’ patent attorneys, Welch and Gulbrandsen, on June 26, 1996. [616, at ¶ 281.] The Examiner’s notes from that meeting indicate that he and the attorneys discussed “all claims” of the application, prior art, and amendments that might overcome the pri- or art. [616, at ¶ 282.] Specifically, the Examiner, Welch, and Gulbrandsen discussed the claims of the '488 application in view of two extant patents — U.S. Patent No. 5,063,221 (“the Nishii patent”), which issued on November 5, 1991, had a filing date of March 29, 1990, and had a foreign priority date of April 5, 1989; and U.S. Patent No. 4,948,789 (“the Slatopolsky patent”), which issued on August 14, 1990, and had a filing date of March 28, 1989. Welch and Gulbrandsen had brought the Nishii patent to the Examiner’s attention in an Information Disclosure Statement dated December 4, 1995. [616, at ¶ 284.] The applicants brought the Slatopolsky to the Examiner’s attention at the June 26, 1996 interview. [616, at ¶ 284.] Following the interview, the Examiner rejected all claims of the application over the Nishii and Slatopolsky prior art. [616, at ¶ 283.]

In response to the Examiner’s rejections of the claims, Welch amended the '488’s application relate-back clause to include a claim for priority to the August 2, 1988 filing date of the '371 application. [616, at ¶ 287 (citing Killworth Trial Tr.2046:23-2047:1; 2050:18; 2052:1-2052:8).] The relate-back clause drew the Examiner’s attention to the fact that “applicants’ priority date antedates the filing dates of the prior art discussed in the interview, namely Nishii * * * and Slatopolsky * * [616, at ¶ 288 (citing Keana Trial Tr.2046:23-2047:1, 2050:10-20150:18, 2052:1-2052:8).] Welch also cancelled claims 5, 6, 10-14, and 19-20, and amended claims 1, 2, 15, and 16. [610, at ¶ 106(f).] In addition, she narrowed claims 1 and 2 in order to distinguish them from the Nishii and Slatopolsky patents. [610, at ¶ 113.] Welch stated that the amendments to the application made the invention “distinguishable” from the Nishii and Slatopolsky prior art. [610, at ¶ 278 (citing Keana Trial Tr. 356:24-357:18).] Welch did not submit affidavits or other evidence showing conception of the invention of a method of administering doxercalciferol to lower serum PTH in SHPT and ESRD patients prior to the filing of the Nishii and Slatopolsky patents. [610, at ¶ 126 (citing Keana Trial Tr. 364:11-24).] Further, Welch did not submit a supplemental oath or declaration when she amended the relate-back clause, as required by the Manual of Patent Examining Procedure (“MPEP”), Sixth Edition, Jan. 1995 at § 1.67(c). [610, at ¶ 134 (citing Killworth Trial Tr.2071:20-2072:18).]

Examiner Criares did not issue an Office Action on the merits in response to the applicants’ amendments; instead, on July 12, 1996, he issued a Notice of Allowability that allowed claim 17 (among others). [610, at ¶ 131 (citing Sofocleous Trial Tr. 1356:22-1357:17, Killworth Trial Tr.2054:l-5, 2060:19-20).] The Notice of Allowability did not include an explicit determination regarding priority of the '488 application at any time during the prosecution of that application. [610, at ¶ 136 (citing Sofocleous Trial Tr. 1357:4-21).]

Defendants argue that because (1) applicants’ relate-back clause improperly failed to file a supplemental oath or declaration, (2) the Examiner did not have evidence that claim 17 was conceived of or reduced to practice in 1988, and (3) the Examiner did not make an explicit determination regarding priority during the prosecution of the '488 application, the '488 application— and the '116 patent that issued from it— should not be entitled to a 1988 priority filing date. [610, at 130-136.] Defendants further argue that, although the Examiner ultimately issued a Notice of Allowability despite his earlier rejections of all claims over the Nishii and Slatopolsky patents, the basis of allowance has nothing to do with a priority date determination, but rather shows that the Examiner believed that the invention of claim 17 was “distinguishable” from the prior art. [610, at ¶ 117 (citing Keana Trial Tr. 360:20-363:4).]

Plaintiffs contend that by drawing the Examiner’s attention to their priority claim, the inventors set up the issue of priority for determination. [616, at ¶ 292.] Plaintiffs argue that the MPEP § 201.08 requires the examiner to make such a determination under these circumstances. [616, at ¶ 292 (citing Killworth Trial Tr.2052:9-14).] Because the Examiner issued a Notice of Allowability for claim 17 (and other claims) after Welch submitted the amended claims, Plaintiffs argue that the Examiner necessarily had to have concluded that the prior art references were overcome by the claim to priority to August 2, 1988 filing of the '371 application. [616, at ¶¶ 294-296 (Killworth Trial Tr.2054:1-9, 2054:15-24, 2058:17-2059:9, 2060:19-2060:20).] Otherwise, Plaintiffs assert, the Examiner could not have allowed claim 17 over the Nishii and Slatopolsky references. Plaintiffs further argue that the Examiner had sufficient time and familiarity with the subject matter of the '488 and '371 applications to substantively consider the claim to priority. [616, at ¶ 298 (citing Killworth Trial Tr.2061:22-2062:6).]

In a prior opinion at the summary judgment stage [496, at 8-10], this Court set forth the principles that govern a court’s assessment of the whether a PTO examiner has signed off on a priority determination. Without repeating the full analysis, the Court reiterates the Federal Circuit’s statement that “[t]he PTO’s own procedures indicate that examiners do not make priority determinations except where necessary.” PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1305 (Fed.Cir. 2008). Of course, when the PTO does render a decision on priority, that decision is entitled to deference from the courts. See id. at 1304. But “[w]hen neither the PTO nor the Board [of Patent Appeals and Interferences] has previously considered priority, there is simply no reason to presume that claims in a CIP application are entitled to the effective filing date of an earlier filed application. Since the PTO did not make a determination regarding priority, there is no finding for the district court to defer to.” Id. at 1305.

The Court noted in its earlier opinion— and reiterates here — that there was no express priority finding by Examiner Criares. The difficulty in this instance is that the Court has no way of determining with any degree of confidence, much less certainty, why no finding was made. Since the Examiner had before him multiple arguments for issuing the Notice of Allowance, some of which were consistent with an implicit finding of a 1988 priority date and others of which were not — for example, the argument that claim 17 is distinguishable from the prior art — there is no way of inferring a priority finding from the Examiner’s silence on the issue. The upshot of the foregoing analysis is that the contested aspects of the priority determination under 35 U.S.C. § 112, ¶ 1 (written description and enablement ) must be assessed without according any deference to the Examiner’s (unstated) views.

4. Written Description — Whether Example 4 of the '371 Application Would Reasonably Have Conveyed the Invention Set Forth in Claim 7 to a POSA in 1988

At trial, Plaintiffs presented evidence that they contend shows that claim 7 is entitled to August 2, 1988 filing date because the '371 application provides a written description the invention. Defendants countered with evidence purporting to show that that the invention described in claim 7 was not sufficiently described by the '371 application, thereby entitling claim 7 only to the 1995 filing date.

As a threshold matter, the Court will restate, and perhaps clarify [see 502, at 13 n. 9], its understanding of the controlling law on the written description requirement. Where, as here, the Defendants have contended that a patent is invalid based on anticipating prior art, the Plaintiffs have “the burden of going forward with evidence * * * that * * * it is not prior art because the asserted claim is entitled to the benefit of a filing date prior to the alleged prior art.” Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed.Cir.2008). This requires the Plaintiffs “to show not only the existence of the earlier application, but why the written description in the earlier application supports the claim” — that is, the existence of “an ancestor” to the patent at issue with a prior filing date that “contains a written description that supports all the limitations” of the claim. Id. Once “the evidence and argument in support of the earlier filing date is * * * before the court, the burden of going forward again shifts to the proponent of the invalidity defense,” and Defendants must convince the court that [Plaintiffs are] not entitled to the benefit of the earlier filing date.” Id. at 1328 (emphasis added). As the Federal Circuit stressed, “ ‘[convince’ is the operative word, because if the court is not persuaded by clear and convincing evidence that [Defendants are] correct,” the Defendants have failed to carry their ultimate burden of persuasion, and their defense of invalidity fails. Id. In short, the “ultimate burden” that is on the challenger to show by clear and convincing evidence that a patent is invalid “never shifts, however much the burden of going forward may jump from one party to another as the issues in the case are raised and developed.” Id. at 1329.

Here, because “the evidence and argument in support of the earlier filing date is * * * before the court, the burden of going forward again shifts to the proponent of the invalidity defense,” and Defendants must convince the court that [Plaintiffs are] not entitled to the benefit of the earlier filing date.” Tech. Licensing Corp., 545 F.3d at 1328; see also Ralston Purina Co. v. Far-Mar-Co., 772 F.2d 1570, 1574 (Fed. Cir.1985) (“A party asserting invalidity based on 35 U.S.C. § 112 bears no less a burden and no fewer responsibilities than any other patent challenger”). “It is elementary patent law that a patent application is entitled to the benefit of the filing date of an earlier filed application only if the disclosure of the earlier application provides support for the claims of the later application, as required by 35 U.S.C. § 112.” In re Chu, 66 F.3d 292, 297 (Fed. Cir.1995).

As the Court previously has explained [see 498, at 11-12], to satisfy the written description requirement, a patent application to which inventors later claim priority (i.e., a parent application) must “contain a written description of the invention and process of making and using it • * *.” 35 U.S.C. § 112, ¶ 1. The written description requirement is satisfied when “the disclosure of the [invention in the parent application] reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed.Cir.2010) (en banc) (citing Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed.Cir.1991)). The test is a flexible one, “requiring] an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art (“POSA”). Based on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed.” Id. The original application need not recite the claimed invention in haec verba — that is, in exactly the same terms as the later application does — but it must do more than merely render the invention obvious. Id. at 1352.

Although the specification “must describe the claimed invention with all its limitations” (Tronzo v. Biomet, 156 F.3d 1154, 1158 (Fed.Cir.1998) (emphasis added)), a failure to “specifically mention a limitation that later appears in the claims is not * * * fatal * * * when one skilled in the art would recognize upon reading the specification that the new language reflects what the specification shows has been invented.” All Dental Prodx, LLC v. Advantage Dental Products, Inc., 309 F.3d 774 (Fed.Cir.2002) (emphasis added). It is sufficient for purposes of the written description requirement that a POSA would find it “reasonably clear what the invention is and that the patent specification conveys that meaning.” Id.; see also Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1571-72 (Fed.Cir.1997) (“a prior application itself must describe an invention, and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought”). In short, the written description must “actually or inherently disclose” each element claim. PowerOasis, 522 F.3d at 1307. Finally, “[compliance with the written description requirement is a question of fact, which, following a bench trial,” is reviewed by the court of appeals for clear error. Tech. Licensing Corp., 545 F.3d at 1332.

Defendants argue that example 4 of the '371 application would not reasonably have conveyed the invention set forth in construed claim 7 to a POSA in 1988, and thus that the '371 application does not sufficiently describe the invention so as to entitle claim 7 to the filing date of the '371 application. Specifically, Defendants presented evidence that the '371 application did not describe three of the four “key elements” of construed claim 7: administration of doxercalciferol to SHPT patients (element two) in a manner that lowered or maintained lower PTH levels (element three) with a lower incidence of hypercalcemia than calcitriol or alfacalcidol (element four).

Plaintiffs acknowledged that at the time the '371 application was filed, the inventors did not have clinical data on the use of doxercalciferol patients in ESRD patients [610, at ¶ 67 (citing Bishop Deposition Tr. 147:6-13, 148:1-14) ]. However, Plaintiffs presented evidence purporting to show that example 4 of the '371 application provided the first written record of Plaintiffs’ desire to evaluate doxercalciferol in patients with SHPT and ESRD [610, at ¶ 67 (citing Bishop Deposition Tr. 134:1-7)] and thus evidenced the conception and reduction to practice of the invention set forth in claim 7 [610, at ¶ 67 (citing Bishop Deposition Tr. 143:3-16,145:19-147:5) ].

a. ESRD

As stated above, example 4 of the '371 application describes a prophetic clinical trial in which doxercalciferol is administered to 30 men and women who have renal disease and are undergoing chronic hemodialysis. [616, at ¶216 (citing Lang-man Trial Tr. 1778:13-16).] Plaintiffs’ and Defendants’ experts agreed that a POSA in 1988 would have understood that patients who have renal disease and are undergoing chronic hemodialysis have ESRD. [616, at ¶ 217 (citing Langman Trial Tr. 1778:10-25; Segre Trial Tr. 937:18-23; Keana Trial Tr. 376:6-8; 565:3-14); .610, at ¶ 80 (citing Segre Trial Tr. 770:24-771:25, 804:4-22, 937:18-938:1; Langman Trial Tr. 1778:2-1779:4).] The Court thus finds that example 4 sufficiently describes this element of claim 7.

b. SHPT

Plaintiffs’ expert Dr. Langman testified that a POSA in 1988 would have understood that patients undergoing chronic hemodialysis (ie., who have ESRD) would have SHPT. [616, at ¶ 35 (citing Langman Trial Tr. 1779:13-1781:14).] Dr. Langman stated that in a randomized double-blind placebo trial like the one described in example 4 of the '371 application, the results of the placebo group provide the POSA with information regarding the disorder with which both patient groups present. [616, at ¶225 (citing Langman Trial Tr. 1776:10-15,1783:10-14).] Here, example 4 explicitly states that the placebo group experienced (1) frequent hypocalcemia and (2) a loss of radial and spinal bone density [616, at ¶¶ 226, 229 (citing Langman Trial Tr. 1785:8-11, 1789:6-20).] Dr. Langman testified that these two conditions would have told a POSA in 1988 that the patients had SHPT. Specifically, Dr. Langman testified that a POSA would have interpreted the term hypocalcemia to be synonymous with SHPT in patients who have ESRD. [616, at ¶ 228 (citing Langman Trial Tr. 1788:16-1789:25).] In addition, Dr. Lang-man testified that a loss of bone density in ESRD patients would have been understood to be a symptom of metabolic bone disease that was caused by elevated PTH in untreated patients with SHPT. [616, at ¶230 (citing Langman Trial Tr. 1789:6-20).] Dr. Langman noted that the FDA-approved label for calcitriol in 1988 stated that it was to be used “for the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis.” [616, at ¶ 231 (citing Langman Trial Tr. 1792:22-1793:11).] Plaintiffs also presented evidence that a POSA in 1988 would have concluded that the patients in example 4 were being treated for SHPT by virtue of the control period prescribed in the example. [616, at ¶¶ 221, 223 (Langman Trial Tr. 1782:16-20).] The control period required that both patient groups “receive a maintenance dose of vitamin D8.” Because vitamin D is used only in ESRD patients to treat SHPT, Dr. Langman testified that the control period would tell a POSA in 1988 that the patients had SHPT. [616, at ¶¶ 221, 223 (Langman Trial Tr. 1782:16-20).]

Defendants argued at trial that nothing in example 4 defines whether the patients have SHPT. [610, at ¶80.] First, Dr. Segre testified that, contrary to Dr. Lang-man’s assertion, the term “hypocalcemia” and “SHPT” in ESRD patients are not synonymous: some ESRD patients would have normal serum PTH levels, and others might have a condition known as tertiary hyperparathyroidism (a condition that is unresponsive to vitamin D therapy). [610, at ¶¶ 89-90 (citing Segre Trial Tr. 761:6-11, 767:6-14, 772:10-13, 773:9-16, 810:5-19, 816:19-820:8, 834:2-17, 962:1-4, 1000:24-1001:5).] In either of those cases, the patients would not have SHPT. [Id.]

Second, Defendants argued that Dr. Langman’s opinion that the control period supports an understanding that the patients have SHPT is an assumption not based on evidence, and is unwarranted. [634, at ¶473.] Dr. Segre testified that example 4 does not state whether the patients were receiving any medications before the control period began, and that it would not necessarily be clear to a POSA that the control period was mandated in order to wash out calcitriol, which would show that the patient group had SHPT. [610, at ¶ 99 (citing Segre Trial Tr. 2450:11-2451:22; Langman Trial Tr. 1782:5-20,1784:6-9).] The Court finds Dr. Segre’s testimony on this point unpersuasive. The control period mandates that all patients receive a maintenance dose of vitamin D8. Vitamin D3 was known in 1988 to be used in the treatment of SHPT but not in the treatment of patients who had normal serum PTH levels (who would have no need for vitamin D treatment) or who had tertiary hyperparathyroidism (for whom vitamin D3 is contraindicated). Therefore, requiring a maintenance dosage of vitamin D3 reasonably would convey to a POSA in 1988 that the ESRD patients described in example 4 would have SHPT.

Third, Dr. Segre testified that some ESRD patients experiencing hypocalcemia may suffer from a condition called osteomalacia, or “aluminum bone disease,” rather than SHPT. [610, at ¶ 91 (citing Segre Trial Tr. 833:3-834:1, 943:21-944:9, 2438:7-9).] Dr. Segre also testified, however, that in 1988, osteomalacia in ESRD patients was “almost always the result of aluminum toxicity.” [635, at p. 23 (citing Segre Trial Tr. 938:1-315).] Dr. Segre testified that patients with aluminum bone disease typically did not have hypocalcemia. [Id.] Plaintiffs argue that, by “logical extension,” patients with osteomalacia in 1988 typically did not .have hypocalcemia. [635, at p. 23.] Because the patients described in example 4 are said to be hypocalcemic, the Court finds that a POSA in 1988 would have understood that the patients were suffering from SHPT and not aluminum bone disease or osteomalacia.

c. Lowering and Maintaining Lowered PTH Levels

Plaintiffs presented evidence purporting to show that example 4 describes and enables the element of claim 7 requiring lowering or maintaining lowered PTH levels. Dr. Langman testified that the goal of treating patients with ESRD and SHPT is to manage their hypocalcemia and prevent the loss of bone mineral density [616, at ¶ 233 (citing Langman Trial Tr. 1792:22-1793:11)], and that in 1988 a POSA would have understood this goal to be linked to lowering PTH levels. This is because hypocalcemia provokes increased PTH levels. [616, at ¶ 235 (citing Langman Trial Tr. 1798:7-1799:2; Segre Trial Tr. 946:18-946:24; Deftos Deposition Tr. 109:20-110:20).] Example 4 states that the treated patient group will have normalized serum calcium levels — ie., levels of serum calcium that are increased from sub-normal to normal levels — and stable radial and spinal bone densities. [616, at ¶ 234 (citing Langman Trial Tr. 1797:1-10).] Dr. Langman testified that a POSA in 1988 would have understood that normalized serum calcium levels and stable radial and spinal bone densities in the treated group are results consistent with lowering and maintaining lowered PTH levels in patients with SHPT. [616, at ¶¶ 236-237 (citing Langman Trial Tr. 1796:21-1800:6).] Dr. Langman testified that this understanding would have been shored up by the contrast of the treated group with the placebo group, which showed frequent hypocalcemia and loss of bone mineral density. [616, at ¶ 237 (citing Langman Trial Tr. 1796:21-1800:22).]

Defendants’ expert Dr. Segre stated that the endpoints identified in example 4 of the '371 application — calcium levels and bone mineral density — do not correlate with serum PTH and would not have told a POSA in 1988 that serum PTH is being lowered and maintained at lower levels. [610, at ¶ 82 (citing Segre Trial Tr. 831:1— 8, 834:18-835:8, 836:24-838:1, 850:7-851:18).] Defendants pointed out that the endpoint in the '116 patent are measurements of serum.PTH levels, and argued that the different endpoints with respect to PTH levels are significant as they speak to what the patients described in the two applications were being treated for. [634, at ¶ 481.] Defendants contend that the bone mineral density measurements that were used as endpoints in example 4 are useful and appropriate analytical techniques for osteoporosis (the condition indicated by examples 2 and 3 of the '371 application). [610, at ¶ 79 (citing Segre Trial Tr. 697:18-20, 773:23-774:2).] Dr. Segre testified that bone mineral density measurements are not reliable predictors for diagnosing and treating SHPT. [610, at ¶¶ 83-87] (Segre Trial Tr. 686:6-692:14, 697:18-23, 777:9-778:4, 778:5-798:4, 972:8-973:14, 974:25-975:5, 979:6-24, 1001:10-1002:23, 2429:17-2430:19, 2507:6-2508:16.) Rather, Dr. Segre testified, bone biopsy and serum PTH measurements were relied upon in the 1970s and 1980s to assess renal osteodystrophy in ESRD patients. [610, at 102 (citing Segre Trial Tr. 839:23854;12).] In sum, Defendants argued that the non-PTH endpoints described in example 4 of the '371 application are not a “reasonable conveyance” of lowered PTH or maintaining lowered PTH [634, at ¶¶ 482-491], and that a POSA would not believe that Dr. Bishop and the other authors were in possession of the invention set forth in claim 7 of the '116 patent when they drafted example 4. (Segre Trial Tr. 799:11-24.)

Plaintiffs presented evidence purporting to show that Defendants’ concerns with respect to the endpoints identified in example 4 are misplaced. Plaintiffs argue that serum calcium, not serum PTH, measurements were the primary method of measuring PTH levels in 1988 [635, at 15 (citing Sherrard Trial Tr. 1094:21-1097:4, 1097:16-1098:4) ] and that the FDA-approved labels for ESRD and SHPT drugs in 1988 said that they were approved for management of hypocalcemia and renal osteodystrophy in ESRD patients, not for “SHPT” or “PTH” [635, at 15 (citing Bishop Trial Tr. 1591:15-23, 1596:8-17).] Indeed, Plaintiffs note that Defendants’ own expert, Dr. Segre, stated that normalizing serum calcium (the endpoint used in example 4) was a key component of the treatment of patients with ESRD and SHPT. [635, at 16 (citing Segre Trial Tr. 2479:2-13).] Further, Defendants’ witness Dr. Sherrard testified that serum calcium was the primary endpoint for measuring the treatment of patients with ESRD and SHPT because, as of 1988, PTH assays were inconvenient. [616, at ¶ 265-266 (citing Sherrard Trial Tr. 1094:21-1097:4, 1097:16-1098:4; Segre Trial Tr. 981:24-982:17).] Finally, Plaintiffs argued that the bone biopsy endpoints that Dr. Segre deemed appropriate were not the only method for monitoring vitamin D treatment of ESRD and SHPT patients that were known to a POSA in 1988. [635, at 16.] Dr. Langman testified that, in 1988, a POSA would have believed bone densitometers to be useful in measuring the loss of bone mineral density in SHPT patients. [616, at ¶ 263 (citing Langman Trial Tr. 1802:3-9, 1802:16-1803:6, 1803:21-1804:16).] Plaintiffs thus contend that Dr. Segre’s assertions with respect to bone biopsy endpoints should be given little weight. [635, at 16.]

Although Defendants’ discussion of the endpoints in example 4 raises some challenging questions in regard to whether the written description is sufficient as to the third element of claim 7, the Court ultimately finds that Dr. Langman’s and Dr. Sherrard’s testimony, taken together, support the conclusion that example 4 reasonably conveys the concept of lowering and maintaining lowered PTH levels. In considering the endpoints argument, it is important to bear in mind that the focus of the patent application as a whole was primarily osteoporosis, and only secondarily, through example 4, patients with renal disease. As Dr. Langman’s testimony makes clear, bone density was a useful measure for both sets of concerns. Moreover, Dr. Langman persuasively explained that a POSA in 1988 would have concluded from the “normalized” serum calcium levels and the stable bone densities in the treated group — contrasted with the frequent hypocalcemia and reduced bone densities of the placebo group — that example 4 described lowering and maintaining lowered PTH levels. Dr. Sherrard, who testified as both a fact witness and an expert and is (like Dr. Langman) a nephrologist, actually provided support for Dr. Lang-man’s explanation by confirming that as of 1988, clinicians used measurements of serum calcium, not PTH, to assess treatment of SHPT. That testimony undercuts Dr. Segre’s opinion that the endpoints were inconsistent with the notion that the inventors adequately conveyed element three. Indeed, Drs. Langman and Sherrard appeared to be on the same page as to the use of serum calcium as a primary endpoint for both safety and efficacy as of 1988.

d. Lower Incidence of Hypercalcemia

Claim 7 requires “lower comparative hypercalcemia at equipotent doses.” [634, at ¶ 492 (citing Langman Trial Tr. 1773:24-1774:10).] The parties dispute whether that element is described by example 4 of the '371 application.

At trial, Defendants first argued that the '371 application does not provide sufficient comparative data or otherwise demonstrate that doxercalciferol is “substantially less toxic” than calcitriol at equipotent doses so as to provide a sufficient written description of the invention set forth in claim 7. [634, at ¶ 498.] Defendants concede that the '371 application states that doxercalciferol has a lower incidence of hypercalcemia than calcitriol and/or alfaealcidol. [634, at ¶ 500.] However, Defendants point out that these statements are not substantiated by any comparative data regarding the relative incidence of hypercalcemia or comparative data regarding equipotent PTH-suppressive doses. [610, at ¶¶ 60-61; 634, at ¶ 500.] Defendants’ expert Dr. Segre testified that example 4’s statement that the treated group experiences an “insignificant incidence” of hypercalcemia would not tell a POSA that the group experienced less hypercalcemia than patients treated with calcitriol or alfaealcidol because “insignificant incidence” is not defined and because no comparative testing of the compounds in ESRD patients was available at that time. [610, at ¶ 93 (citing Segre Trial Tr. 864:19-866:1).] Similarly, Dr. Segre testified that example 4’s statement that the placebo group — which was described as receiving a “normal” intake of dietary calcium- — experienced “frequent hypocalcemia” is uninformative, since example 4 is silent as to the baseline levels of serum calcium in the placebo and treated groups and does not explain what is a “normal” intake of dietary calcium. [610, at ¶ 94 (citing Segre Trial Tr. 801:2-13, 860:22-25, 862:3-11).]

Even if Dr. Segre’s criticisms concerning the lack of data in example 4 are well founded, the test under § 112 is not how much data a parent patent application provides to substantiate the invention set forth in a later patent application, but rather what a POSA would understand the parent application to reasonably convey. The Court thus examines whether, notwithstanding the lack of hard data, the '371 application would reasonably convey claim 7 of the '116 patent to a POSA in 1988.

Defendants’ expert Dr. Sherrard testified that a POSA in 1988 did not understand the extent to which the dosing of calcitriol and alfacaleidol related to the incidence of hypercalcemia. [610, at ¶ 9] (citing Sherrard Trial Tr. 1092:3-1094:20, 1097:5-1098:16, 1099:16; Langman Trial Tr.l987:9-23).] Defendants showed that scientists in 1988 thought it was necessary or desirable to administer a certain dosage of vitamin D in ESRD patients to reduce PTH levels to at or below twice the upper limit of normal PTH. (Sherrard Trial Tr. 1098:5-12; Langman Trial Tr.l971:161972:12.) At those levels, however, scientists in 1988 did not realize that they were over suppressing PTH, which led to adynamic bone disease and hypercalcemia. (Sherrard Trial Tr. 111:7-1114:9; Lang-man Trial Tr.l954:16-1955:19, 1987:23.) Dr. Sherrard testified that as doctors learned how to dose those drugs properly, the incidence of hypercalcemia was largely ameliorated. [610, at ¶ 9 (citing Sherrard Trial Tr. 1119:8-13).

Dr. Sherrard testified that in the early 1990s he published his conclusions from a trial (“the Toronto trial”) that showed that calcitriol could be dosed to achieve a target range of PTH — 150 to 300 pg/mL — that avoided adynamic bone disease and resulted in a far lower incidence of hypercalcemia than previously associated with the drug. (Sherrard Trial Tr. 1118:5-1123:5.) Dr. Sherrard testified that he presented his conclusions to Dr. Jack Coburn in 1992 (Sherrard Trial Tr. 1121:7-1123:5), and that, in 1994, Coburn co-drafted with Dr. Bishop the treatment protocol for Bone Care’s H-106 clinical trial of doxercalciferol in ESRD patients (Bishop Trial Tr. 1661:2-9, 1658:20-22.) Dr. Sherrard testified that Dr. Coburn used the same dosing protocol in the H-106 trial that Sherrard had used in the Toronto trial and presented to Coburn. (Bishop Trial Tr. 1659:24-1662:3; Sherrard Trial Tr. 1127:21-1129:15.)

Plaintiffs responded that much of Dr. Sherrard’s testimony regarding the possible safe administration of calcitriol is inadmissible. Plaintiffs contended that Dr. Sherrard’s testimony regarding his communications with Dr. Coburn is inadmissible as hearsay and that the Court should disregard it because Defendants did not provide any documentary corroboration of those communications. [635, at p. 5.] Plaintiffs also contended that Dr. Sherrard’s testimony regarding oversuppression of PTH as a cause of adynamic bone disease or hypercalcemia is inadmissible because Dr. Sherrard did not discuss this subject in his expert report and it is improper opinion testimony from a fact witness. [635, at p. 2.] Plaintiffs further argued that even if Dr. Sherrard’s testimony is admitted, it has no bearing on the issue at the heart of claim 7 — which is not whether calcitriol can be administered safely, but whether treatment with doxercalciferol results in a lower incidence of hypercalcemia than ealcitriol. [635, at pp. 5-6.] Plaintiffs presented evidence that even if doxercalciferol can oversuppress PTH so as to cause adynamic bone disease, ealcitriol more commonly leads to those results. [635, at 6 (citing Langman Trial Tr. 1942:4-19).] And, Plaintiffs argued, what matters ultimately is whether ealcitriol or alfacalcidol more frequently induces hypercalcemia. [635, at p. 6.]

Plaintiffs’ expert Dr. Langman provided credible testimony that the '371 application conveyed the key element of lower incidence of hypercalcemia. First, Dr. Langman testified that, based on the prior art, ealcitriol and