Case IPR2015-
`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owner
`
`Patent No. 8,729,094
`Issue Date: May 20, 2014
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1021)
`
`DECLARATION OF WILLIAM P. McGIDRE
`
`4121499_1.docx
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1021
`
`Exh. 1021
`
`
`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owner
`
`Patent No. 8,729,094
`Issue Date: May 20, 2014
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1021)
`
`DECLARATION OF WILLIAM P. McGIDRE
`
`4121499_1.docx
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1021
`
`Exh. 1021
`
`
`
`I, WILLIAM P. McGUIRE, hereby declare as follows:
`
`1.
`
`2.
`
`3.
`
`I am a U.S. citizen and a resident of the State of Virginia.
`
`I am board certified in Internal Medicine and Medical Oncology.
`
`I am a medical oncologist currently employed at Virginia
`
`Commonwealth University (VCU) in Richmond, Virginia, as a Professor of
`
`Internal Medicine and Director of the Phase I Solid Tumor Program in the Massey
`
`Cancer Center at VCU. I have held this position since December 2, 2014. In that
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`capacity, and among my other responsibilities, I act as a mentor to younger faculty
`
`who wish to develop careers in cancer drug development.
`
`4.
`
`I have worked for over 40 years in both academic medicine and in the
`
`private medical sector. During that time, one constant has been my work in clinical
`
`trials and developmental therapeutics, a field of investigation in which new agents
`
`are evaluated clinically in cancer patients.
`
`5.
`
`After completion of my medical training at Baylor College of
`
`Medicine, (1971), Yale New Haven Hospital (1973), and the National Cancer
`
`Institute (NCI) (1976), I initially worked for the NCI as a Senior Investigator with
`
`responsibility for overseeing grants and contracts to multiple academic centers that
`
`were running Phase I and Phase II clinical trials (1976-1979). I left the NCI to
`
`accept a position at the University of Illinois as the Chief, Division of Medical
`
`Oncology with a rank of Assistant Professor of Medicine (1979) and Associate
`
`4121499_ 1.docx
`
`Exh. 1021
`
`
`
`Professor of Medicine (1982). It was during this time that in addition to my
`
`clinical, administrative, and teaching responsibilities, I became a member of the
`
`Gynecologic Oncology Group
`
`(GOG).
`
`I previously had had oversight
`
`responsibility for the GOG during my tenure at NCI and was not legally allowed to
`
`become a member of the group until I had vacated this position for two years. The
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`GOG is a grant-funded consortium of academic institutions dedicated to improving
`
`treatment of female pelvic cancers. I worked with GOG (1982-2013) holding
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`several key positions including co-chairman of the Ovarian Cancer Committee and
`
`Chairman of the Developmental Therapeutics Committee, which was responsible
`
`for all Phase I and Phase II trials for that group.
`
`6.
`
`In (1985), I moved to Johns Hopkins University as Associate
`
`Professor of Oncology (1985), Associate Professor of Otolaryngology, Head and
`
`Neck Surgery (1986), Associate Professor of Medicine (1990) and Associate
`
`Professor of Gynecology and Obstetrics ( 1990). I also became a member of the
`
`Phase I Committee in the Johns Hopkins Oncology Center. It was during the
`
`conduct of one of those Phase I studies that I identified paclitaxel (Taxol®) as an
`
`active agent in ovarian cancer. I subsequently performed the Phase II study in
`
`ovarian cancer confirming its activity, followed by a Phase I study of paclitaxel
`
`and cisplatin showing the safety of this combination therapy. I next took this
`
`two-drug regimen to the GOG and oversaw a Phase III trial of that combination,
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`2
`
`Exh. 1021
`
`
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`showing that it outperformed the current standard of care for ovanan cancer
`
`thereby establishing a new standard treatment regtmen for ovarian cancer. I
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`remained at Johns Hopkins until (1993). The rest of the details of my professional
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`career can be found in my current cv which I understand is provided as
`
`Exhibit 1022.
`
`7.
`
`I have not performed specific trials of anti emetics in general, or
`
`setrons in particular. However, the principles of data analysis from clinical studies
`
`of anti emetics are the same as those employed in the many studies I have designed
`
`and participated in. Moreover, as a practicing medical gynecological oncologist, I
`
`am acutely aware of the side effects of highly emetogenic chemotherapies, such as
`
`cisplatin, and I use antiemetics in my practice. I am well aware of the literature
`
`regarding the setrons in general.
`
`8.
`
`I have been retained by Lerner, David, Littenberg, Krumholz &
`
`Mentlik, LLP ("counsel") to provide my opinions in the fields of adjunct therapy for
`
`chemotherapy, and Phase I and Phase II clinical trial design and data analysis in
`
`drug development. I have read and understood U.S. Patent No. 8,729,094 ("the
`
`'094 Patent") (Exh. 1001), as well as all other references discussed in this
`
`declaration. I am being compensated for my time in an amount consistent with my
`
`customary consulting fee, and my compensation is not contingent on my opinion or
`
`the outcome of this proceeding.
`
`3
`
`Exh. 1021
`
`
`
`I.
`
`A PERSON OF ORDINARY SKILL IN THE ART
`9.
`I understand from counsel that patents such as the '094 Patent are
`
`neither addressed to experts nor to laymen; rather they are addressed to persons of
`
`ordinary skill in the relevant art (a "POSA") at the time of the effective filing date
`
`of the application, which I understand to be January 30, 2003. I also understand
`
`that this is a theoretical person with knowledge of all of the relevant literature and
`
`practices. I also understand from counsel that factors relevant to the level of skill in
`
`the art include, without limitation: the educational level of the inventor, the types
`
`of problems encountered in the relevant area, prior art solutions to those problems,
`
`the rapidity with which innovations are made; the sophistication of the technology,
`
`and the educational level of active workers in the field.
`
`10.
`
`I understand from counsel that there was a Trial between the parties
`
`to this IPR on other patents in the '094 Patent's family, and that in that trial,
`
`Petitioner and the Patent Owner took various positions on who a POSA would be. I
`
`did not participate in that trial and do not know the issues in that trial, but I
`
`understand from counsel that the claims at issue there were directed to
`
`formulations similar to the formulations recited in claim 22 of the '094 Patent, but
`
`the claims were not directed to methods of treating chemotherapy induced nausea
`
`and vomiting ("CINV"). Certainly, regarding the subject matter of the '094 Patent,
`
`4
`
`Exh. 1021
`
`
`
`the POSA would have to have significant formulation knowledge and experience
`
`and/or access to experienced people who did.
`
`11. My reading of claim 22, however, is that it is directed to a method of
`
`medical treatment involving people undergoing chemotherapy. Therefore, I think
`
`that a POSA would also need to include an oncologist or other medical specialist
`
`with an advanced degree, such as a Pharm.D. or M.D., with several years of
`
`experience addressing
`
`the side effects of chemotherapy. Such medical
`
`professionals would clearly understand and be able to assess the medical and
`
`pharmaceutical literature relating to the drugs and methods that could be employed
`
`in treating CINV, and other side effects of chemotherapy.
`
`12.
`
`I consider myself to be a person of greater than ordinary skill in the art
`
`pertinent to what I consider the principal focus of the invention claimed in the
`
`'094 Patent, i.e., the administration of a drug to treat a condition. However, as
`
`regards other aspects of the claimed invention, I would consult and rely heavily on
`
`those more specifically involved with the formulation issues, when addressing
`
`these aspects of the claims. Moreover, because of my work experiences and
`
`men to ring of more junior physicians, and my knowledge of the literature from the
`
`relevant time period, I believe that I am well situated to understand what a person
`
`of ordinary skill in the art would have known and understood at the relevant time.
`
`5
`
`Exh. 1021
`
`
`
`II. THE '094 PATENT AND 5-HTJ ANTAGONISTS
`13. The specification of the '094 Patent (Exh. 1001) mostly discusses
`
`certain storage-stable palonosetron formulations. Palonosetron is a 5-HT3 , or
`
`5-Hydroxytryptamine (aka serotonin) receptor antagonist, which is a class of
`
`pharmaceutically active drugs that can bind to the 5-HT3 receptors in the central
`
`nervous system as well as receptors in the gastrointestinal tract that are associated
`
`with the afferent fibers of the vagus nerve. By binding to these receptors,
`
`palonosetron and other 5-HT3 receptor antagonists can prevent the binding of
`
`naturally occurring neurotransmitters, and specifically serotonin. The results of this
`
`blockade can be profound. In the context of treating CINV, 5-HT3 plays a major
`
`role. Certain chemotherapeutic agents cause enterochromaffin cells in the
`
`gastrointestinal tract to release serotonin, which can bind to 5-HT3 receptors
`
`triggering neural signals via vagal afferent nerve fibers to the chemoreceptor
`
`trigger zone and vomiting center located in the brain near the 4th ventricle. Vagal
`
`efferent impulses then lead to stimulation of the gut, leading to retching and
`
`vomiting. Certain chemotherapeutic agents may also cross directly into the central
`
`nervous system, directly stimulating the vomiting center and chemoreceptor trigger
`
`zones. Binding the 5-HT3 receptors can reduce these neural impulses directly and
`
`indirectly thus inhibiting the efferent vagal signals and reducing the impulse to
`
`retch and vomit.
`
`6
`
`Exh. 1021
`
`
`
`14. By January 29, 2003, a number of drugs in this class were known, and
`
`FDA approved in this country, for use in treating CINV, including: ZOFRAN®
`
`( ondansetron HCl), KYTRIL ® (granisetron HCl), and ANZEMET® ( dolasetron
`
`mesylate). (Exhs. 1015-1017.) These were all designated as "setrons" because of
`
`the common suffix in their names. Palonosetron HCl was another, later setron and
`
`5H-T3 receptor antagonist. All were effective, and as a group, by 2003, they had
`
`become part of the standard of care for abrogating chemotherapy induced emesis.
`
`(See Exhs. 1013, 1027.)
`
`15.
`
`I understand from counsel that questions relating to the patentability
`
`of claims 22 through 30 are at issue in this proceeding. I believe a POSA would
`
`read claim 22 the same way that I do; that is, as a method of treating CINV by
`
`administering 0.25mg of palonosetron by IV to a patient before administering
`
`chemotherapy. Claim 22 has many other recitations about other things, including
`
`tonicity, concentration, and stability. But, in my opinion, these would not be
`
`considered very relevant to a treating physician of ordinary skill in the art when it
`
`comes to administering the drug to a patient.
`
`16.
`
`Just as an example, the claim seems to require that the formulation
`
`used in the method have a 24-month shelf life. But that would be totally irrelevant
`
`to a POSA's decision to treat a patient with palonosetron, and the method chosen
`
`for doing so. Although a doctor would not knowingly inject a patient with an
`
`7
`
`Exh. 1021
`
`
`
`expired drug, it would not matter whether the patient was treated with a
`
`formulation having a 24-month shelf life, or a formulation made yesterday that
`
`expires tomorrow, so long as the drug being administered had not already passed
`
`its expiration date. In fact, specialty pharmacies, which would be most likely to use
`
`drugs such as those at issue here, typically would not keep a large inventory of any
`
`drug due to storage space and cost of maintaining such an inventory.
`
`17. Moreover, while I am no expert in drug formulation, I know from
`
`personal experience that all of the FDA-approved setrons were sold in relatively
`
`small volume unit doses, allowing them to be injected in a matter of seconds. Some
`
`were also available for oral administration. Based on my general familiarity with
`
`the pharmaceutical products used in my field, and my review of the PDR records,
`
`these prior setrons were sterile, isotonic, and made with what even I know are
`
`reasonably well-known excipients -
`
`like salt, mannitol, and citric acid/citrate. In
`
`this regard, it is not uncommon for oncologists and other medical professionals to
`
`have knowledge of formulations that they deal with on a regular basis. And there
`
`are few drugs used in oncology today that are in some form of aqueous solution.
`
`One of these with which I am quite familiar is paclitaxel, which was nearly shelved
`
`in terms of clinical development due to a lack of solubility. All formulations must
`
`have a concentration and a pH (all liquid formulations would), and all would be a
`
`8
`
`Exh. 1021
`
`
`
`function of the dose and the volume used. So the formulation elements claimed
`
`here are in my opinion, conventional.
`
`18. Everything I reviewed in the preparation of this declaration suggests
`
`that there would not have been any significant formulation issues that would
`
`impact the claimed method. Indeed, Patent Owner made statements to the press
`
`that IV palonosetron for treating CINV had been a success in preclinical, Phase I
`
`and Phase II trials. (Exhs. 1033-1035.) It also informed the world that a Phase III
`
`trial was nearing completion, and that submission of a new drug application to the
`
`FDA was itnrninent. (Exh. 1033.) In my opinion, and based on my experience,
`
`Patent Owner would not make such statements, and the FDA would not have
`
`approved the Phase III trial, unless there was at least a reasonable expectation of
`
`safety and efficiency. And there was no mention of formulation or dosing
`
`issues - or, in my experience, if there were such issues, they would be something
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`reported early and often. Indeed, paclitaxel was formulated in cremophore, a
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`detergent that was necessary because of the poor water solubility of the active
`
`drug. Cremophore was known to cause hypersensitivity reactions, and some were
`
`so severe that patient deaths resulted. That issue was brought up in most of the
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`early papers and abstracts about paclitaxel.
`
`19.
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`Published preclinical data, as well as published accounts of Phase I
`
`and Phase II clinical studies, disclosed an effective dosing range and expressly
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`9
`
`Exh. 1021
`
`
`
`indicated that palonosetron was safe across the entire range tested. (Exhs. 1012,
`
`1018, 1019.) All of this suggests that the formulation was not an issue when it
`
`came to the method of treating CINV.
`
`20. As to the patentability of the method, I believe a POSA would have
`
`difficulty understanding how it could even be argued that the claimed method was
`
`not already disclosed in the art. For example, Berger, U.S. Patent No. 5,202,333,
`
`disclosed palonosetron, that it could be used for treating CINV, and that it could be
`
`formulated as an IV formulation with citric acid and dextrose. (See Exh. 1010 col.4
`
`11.33-45, col.lO 11.6-13, Ex.l3, col.28 1.54 to co1.29 1.12.) It even taught giving
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`palonosetron before administering the chemotherapy. (ld. col.31 1.5-15.)
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`21. Moreover, as discussed in more detail below, Eglen (Exh. 1011) and
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`Chelly (Exh. 10 12) were preclinical and Phase II clinical studies, which taught
`
`administering palonosetron to a patient undergoing chemotherapy to prevent
`
`CINV, or partial prevention of postoperative nausea and vomiting ("PONV"),.
`
`These studies were published in 1995 and 1996, respectively, many years before
`
`the '094 Patent was filed.
`
`22. As for the particular dose recited in the claims, arriving at a particular
`
`dose would be no more than routine, where the preclinical and Phase II data were
`
`in agreement and suggested that virtually any dose above about 0.07 milligrams
`
`would work as well as doses 1 0-fold higher.
`
`10
`
`Exh. 1021
`
`
`
`III. THE STATE OF ART AT 5-HT3
`TREATMENT OF CINV BY JANUARY 29, 2003
`23. By January 29, 2003, selective 5-HT3 receptor antagonists, a class of
`
`drugs including the "setrons," generally had become the standard first-line therapy
`
`for treating CINV. (See Exh. 1027, at 237.) The American Society of Clinical
`
`Oncology ("ASCO") Antiemetic Guidelines were published in 1999, and these
`
`described serotonin antagonists as being "largely responsible for the ease of use
`
`and high effectiveness of antiemetic in clinical practice." (Exh. 1013, at 2974.) I
`
`understand from counsel that both qualify as prior art to the '094 Patent. The
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`ASCO guidelines recommended that, at equivalent doses, serotonin receptor
`
`antagonists have equivalent safety and efficacy and can be used interchangeably
`
`based on convenience, availability, and cost. (ld. at 2974). As for drug schedule,
`
`the guidelines recommended that single doses of antiemetics, as compared to
`
`multiple doses, are effective and are preferred for both convenience and cost. (!d.
`
`at 2975-76 ("A single-dose regimen using the lowest fully effective dose can
`
`provide economic benefit and the potential for the fewest side effects.").) It also
`
`found oral and IV agents to be equally effective. (!d. at 2976.) Thus, using 5-HT3
`
`receptor antagonists as antiemetics in treating CINV was well established prior to
`
`this current patent.
`
`11
`
`Exh. 1021
`
`
`
`IV. EGLEN - PRECLINICAL STUDIES
`IN RECOGNIZED ANIMAL MODELS
`In Eglen, adult male ferrets were given 0.1-100f.!g/kg [ 0.013-1.3 mg] 1
`24.
`
`of palonosetron by IV 30 minutes prior to administration of the chemotherapeutic
`
`agent cisplatin. Adult male dogs were given palonosetron 0.3-300J..Lg/kg
`
`[0.012-12.0mg] by IV 120 minutes prior to administration of chemotherapy. Both
`
`dogs and ferrets were also dosed with ondansetron as a comparator. In a
`
`companion experiment, dogs were also pretreated with either drug at various time
`
`intervals prior to chemotherapy administration, no longer than 24 hours prior to
`
`administration of cisp1atin, in an experiment designed to examine the duration of
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`antiemetic activity. (See Exh. 1011, at 861.)
`
`25.
`
`Cisplatin, when administered to dogs and ferrets, produces an emetic
`
`and behavioral profile which most closely resembles the human clinical syndrome.
`
`(!d. (citations omitted).) "The present study has shown that RS 25259-197,
`
`1 For the Board's convemence, following each dose level reported herein, a
`
`conversion to a corresponding human dose in milligrams is provided. I understand
`
`that these doses in milligrams were calculated by Dr. David Frame, a Phann.D.,
`
`with knowledge of such conversion factors. It is not unusual for those involved in
`
`drug development to make such conversions when using well-established models
`
`for a particular condition. But I did not perform the calculations myself.
`
`12
`
`Exh. 1021
`
`
`
`administered intravenously or orally, potently inhibits cisplatin induced emesis in
`
`both the ferret and dog." (!d. at 865.) "In summary, RS 25259-197 appears to be a
`
`novel, orally active 5-HT3 receptor antagonist that is more potent and has a longer
`
`duration of action than either ondansetron or granisetron." (!d.)
`
`26. The data clearly shows that the inhibitory effects observed in Eglen
`
`began to plateau somewhere between about I and lOJ.Lg/kg [0.013-0.13mg], and
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`shows that at higher doses of 10 and 30~g!kg [0.13-0.4mg], respectively, toxicity
`
`was greater without greater efficacy. Thus, somewhere between about 1 and about
`
`lO~g/kg [0.013-0.13mg], the use of additional palonosetron would not be expected
`
`to provide significant additional inhibition. (Jd. at 863, Fig.5.) That point of
`
`diminishing returns is reached at a relatively low level of palonosetron exposure,
`
`something that is consistent with its potency.
`
`27. A similar phenomenon was observed in dogs, the data for which is
`
`illustrated in Eglen's Fig. 6. (!d. at 863.) The top graph in Fig. 6 shows the
`
`inhibitory effects of IV palonosetron on dogs for doses of 0.3J.lglkg-100J.Lglkg
`
`[0.0 12-4.0mg]. A significant increase in inhibition is illustrated again at lJ.lg/kg
`
`[0.04mg], and a similar plateauing is observed at higher doses.
`
`28.
`
`Fig. 6 also provides data for ondansetron, which illustrates a similar
`
`plateauing effect. However, the plateau is at a much higher dose, which is
`
`reflective of the greater potency of palonosetron as compared to the other setrons
`
`13
`
`Exh. 1021
`
`
`
`which have significantly less potency. Thus, Eglen would teach a POSA that
`
`palonosetron is significantly more potent than ondansetron.
`
`29. Eglen clearly establishes that it was known to use palonosetron for the
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`treatment of CINV both orally and by IV, and that palonosetron was both more
`
`potent and had a longer duration of action than pre-existing commercially available
`
`setrons. It also established a starting point for effective doses in humans of
`
`between about 1 and lOJ.Lglkg [0.013-0.13mg], based on the ferret data, and a range
`
`of likely human doses of between about 3J.Lg/kg and lOJ.Likg [0.12-0.4mg] based on
`
`the dog data.
`
`V. CHELLY - PHASEIIHUMANDATA
`30. Chelly et al. is an abstract published in the September 1996 journal,
`
`"Anesthesiology." (Exh.l012.) Chelly reports the results of a Phase ll clinical
`
`study in humans where palonosetron was administered orally to 350 patients to
`
`prevent PONY following laparoscopic hysterectomy. Palonosetron was dosed at
`
`0.3, 1.0, 3.0, 10.0, and 30Jlg/kg [0.021mg, 0.07mg, 0.21mg, 0.7mg, and 2.1mg] or
`
`placebo. Patients received the study medication one to two hours prior to surgery.
`
`31.
`
`"Compared to
`
`the placebo, RS-25259 [palonosetron]
`
`increased
`
`significantly the percentage of patients who elicited CR [complete response or
`
`complete absence of vomiting] (37%, 58%, 52%, 59%, and 53% vs 33%).
`
`RS-25259 therapeutic effectiveness reached a plateau at a dose of 1 Jlg/kg
`
`14
`
`Exh. 1021
`
`
`
`[0.07mg]. Except for 0.3Jlg/kg [0.021mg], RS-25259 induced a significant
`
`reduction in the frequency of severe nausea episodes as compared to placebo."
`
`(!d.) "This data demonstrates that a minimum dose of lJ.!g/kg [0.07mg] RS-25259
`
`orally administered is an effective and safe treatment for the prevention of PONV
`
`in patients undergoing laparoscopy surgery." (!d.)
`
`32.
`
`I have read and understand the declaration of Dr. Frame, and as an
`
`M.D. and part of a group looking into dosing of a drug, I would rely heavily on a
`
`formulator and Pharm.D. 's opinion on adjusting doses for IV administration versus
`
`oral administration. In this regard, there seems to be good agreement between
`
`Eglen and Chelly on the starting doses as well as the plateauing effects of the
`
`doses. Accordingly, in my opinion, picking any dose close to the plateau would
`
`have been obvious.
`
`Choosing a dose significantly higher would seem
`
`counterintuitive as this would not have improved the sought after effect and would
`
`have had a greater likelihood of toxic manifestations.
`
`33.
`
`In my experience, the agreement between predictive models and
`
`actual human testing, like this, would provide a POSA with enhanced confidence
`
`in the predictive power of this early clinical and preclinical work. Taking these
`
`references together as a POSA clearly would do (indeed a POSA would look at all
`
`available data), it is clear that palonosetron at and above a dose of about l.OJlg/kg
`
`[0.07mg], administered either orally or by IV, would be expected to be effective
`
`15
`
`Exh. 1021
`
`
`
`for both PONV and CINV. The preclinical and clinical data from Eglen and Chelly
`
`also demonstrate the safety of palonosetron upon administration. Additionally, the
`
`Chelly study is commensurate with the preclinical studies in both ferrets and dogs
`
`making a POSA very comfortable with both efficacy and toxicity of a dose of
`
`around 1.0 J.lglkg [0.07mg] or more for prevention of both PONV and CINV.
`
`34. Determining a dose for further study, or for a commercial product,
`
`based on data like that presented by Eglen and Chelly, is an everyday,
`
`garden - variety exercise - one faced by virtually every group of formulators,
`
`medical doctors, and clinicians involved in drug development. In fact, in my
`
`experience and what, in my opinion, would be the experience of a POSA, there is
`
`better agreement here than one normally finds in such data. Indeed, I think a POSA
`
`would be particularly encouraged here, because the data line up so well, even
`
`though one study was PONV using an oral dose and the other study looked at
`
`CINV using IV dosing. Indeed, in practical terms, Chelly found that efficacy
`
`plateaued at 1J.!g/kg [0.07mg] and said so. Thus, dosing below 1J.!g/kg [0.07mg]
`
`would already be expected to be suboptimal. And, there would be no reason to
`
`dose at the upper end of Chelly's disclosed range, even if there would be little
`
`harm in doing so. Indeed, that would only raise the cost of the drug for little or no
`
`additional therapeutic benefit. It would also pointlessly expose the patient to risks
`
`of possible side effects, albeit relatively mild ones. Thus, in my the effective
`
`16
`
`Exh. 1021
`
`
`
`starting dose suggested by the combined teachings of Eglen and Chelly to a POSA
`
`is about 1 J..Lg/kg [0.07mg] or more along the plateau.
`
`35.
`
`In my experience, many chemotherapeutic agents, and other drugs
`
`where dosing is critical, are actually administered based on weight or body surface
`
`area. Palonosetron is given at a single fixed dose, like the other setrons. That dose
`
`will be given to a 1 OOlb woman and to a 250lb man. Based on this fact alone, a
`
`POSA would expect that administering more, or slightly less, than the claimed
`
`amount of palonosetron would provide equivalent results. This flat dosing is
`
`typical of drugs where there is a very wide therapeutic index, a broad range of
`
`doses that achieve the desired effect without causing undue toxicity
`
`36. This is about as good as it gets for drug designers. For the reasons
`
`emphasized above, the collective preclinical and clinical testing had already
`
`established a reasonable expectation of success. Any number of doses would likely
`
`work for the intended purpose. So long as a sufficient minimum dose was
`
`established -
`
`something that could be established or predicted easily -
`
`selecting
`
`a dose would involve the normal balance of efficacy (which was expected to all be
`
`about the same based on the established plateau), safety, cost, and other normal
`
`formulation factors. In my opinion, establishing a commercial dose with this
`
`foundation is the epitome of routine experimentation. And here, in my opinion, a
`
`POSA would likely select a dose of 1 J..Lglkg [0.07mg] or higher for the reasons I
`
`17
`
`Exh. 1021
`
`
`
`just explained. Based on the data and balancing the reasons just discussed,
`
`particularly in view of Chelly, a dose around 3.0~g/kg [0.21mg], or more, would
`
`likely be selected for further study or commercialization. That said, any selection
`
`along the plateau would have been equally expected to be safe and effective.
`
`37. Finally, I understand that during trial, Patent Owner argued the
`
`primacy of another reference of a Phase II study for PONV; Tang. (Exh. 1019.) I
`
`have also been told by counsel that Patent Owner argued that Tang, as the only
`
`peer-reviewed article relating to human testing at the time, would supplant prior
`
`animal data, and Chelly, which was an abstract. First, I don't know of anyone in
`
`drug development who would ever ignore data unless it was somehow considered
`
`invalid or unreliable, and I see nothing to suggest that this would be the case for
`
`Eglen or Chelly.
`
`38.
`
`Second, Tang's statement suggesting only 30~g/kg shows efficacy is
`
`not at all clear. The 30~g/kg dose seems more to me an outlier than a well-
`
`supported conclusion. In fact, Tang was eventually proven wrong - doses that are
`
`10% of the dose Tang advocated work just fine, just as Eglen and Chelly taught. I
`
`would not think of Tang, and particularly this teaching, as a "teaching away."
`
`Instead, I would take Tang at its word. More particularly, as a medical oncologist,
`
`and in particular, a medical gynecological oncologist, I would take Tang as
`
`teaching, at most, that palonosetron at any dose was not particularly useful in
`
`18
`
`Exh. 1021
`
`
`
`treating PONV in hysterectomy patients. (Exh. 1019, at 465 RS-25259 seems to be
`
`of rather limited benefit at all doses in this very high risk population. I would take
`
`that statement, and Tang's conclusion that "RS-25259 30 J.lg/kg was effective in
`
`preventing PONV in women undergoing major gynecologic surgery" (id. at 466),
`
`as a very limited and narrow teaching at most, and I would do so on the assumption
`
`that I was taking Tang in complete isolation from other data. I would not take it as
`
`a broad teaching away from the use of lower doses of palonosetron as an
`
`antiemetic in other contexts, or as a rebuke of Chelly or Eglen.
`
`39.
`
`Indeed, my reading of Tang is that its data is actually supportive of
`
`Chelly -
`
`it does not teach away from it. The ranges tested in Tang and Chelly are
`
`nearly the same, as is the resulting data showing the same plateauing behavior seen
`
`in Chelly, and indeed in Eglen, at about the same dose level of about 0.07mg. Also,
`
`Tang specifically acknowledged Chelly, and when it did, it did not suggest that
`
`Chelly was wrong. (Exh. 1019, at 466.)
`
`40.
`
`I also understand that one of the claims of the '094 Patent dependent
`
`claim 25, discusses treating delayed emesis. Nothing in the '094 Patent explains
`
`what delayed emesis is. But from my experience, it generally refers to the
`
`commencement of emesis more than 24 hours after beginning chemotherapy. The
`
`'094 Patent does not describe how its method of administering palonosetron would
`
`be changed to treat delayed emesis versus acute emesis. And, for a new patient,
`
`19
`
`Exh. 1021
`
`
`
`one for which there is no prior experience, a doctor would have no idea whether
`
`the patient would develop emesis at all, let alone acute or delayed emesis. In either
`
`event, the doctor would treat this patient the same giving them the same amount of
`
`palonosetron before chemotherapy begins.
`
`20
`
`Exh. 1021
`
`
`
`I hereby declare under penalty of perjury under the laws ofthe United States
`
`of America that the foregoing is true and correct, and that all statements made of
`
`my own knowledge are true and that all statements made on information and belief
`
`are believed to be true. I understand that willful false statements and the like are
`
`. punishable by fme or imprisonment, or both (18 U.S.C. § 1001).
`
`~ez. fl· "":~
`
`William P. McGuire
`
`4 121462_Ldocx
`
`21
`
`Exh. 1021
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