Ex Parte 7148359 et al

Patent Trial and Appeal Board

Dec 29, 2015

95000570 (P.T.A.B. Dec. 29, 2015)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
95/000,570 09/23/2010 7148359 1781
7590 12/29/2015
ABBOTT LABORATORIES
100 ABBOTT PARK RD
D377/AP6A-1
ABBOTT PARK, IL 60064
EXAMINER
HUANG, EVELYN MEI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
12/29/2015 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
95/002,019 06/15/2012 7148359 7,148,359 reexamination 6786
7590 12/29/2015
ABBOTT LABORATORIES
100 ABBOTT PARK RD D377/AP6A-1
ABBOTT PARK, IL 60064
EXAMINER
HUANG, EVELYN MEI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
12/29/2015 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

BRISTOL-MYERS SQUIBB CO. and PUBLIC PATENT
FOUNDATION
Requesters and Respondents

v.

ABBVIE Inc.
Patent Owner and Appellant
____________

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2
Technology Center 3900
____________

Before JAMES T. MOORE, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the Patent Owner from the
Patent Examiner’s final rejection of claims 1, 2, and 4–10 in the
above-identified inter partes reexamination of United States Patent
7,148,359 B2. The Board’s jurisdiction for this appeal is under
35 U.S.C. §§ 6(b), 314, and 315. We affirm.

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

2

I. BACKGROUND
The patent in dispute in this appeal is US 7,148,359 B2 (“the
’359 Patent”) which issued Dec. 12, 2006. The real party in interest
and assignee is AbbVie Inc. (“Patent Owner”). Appeal Br. 2.
A request for inter partes reexamination of the ’359 Patent
under 35 U.S.C. §§ 311–318 and 37 C.F.R. §§ 1.902–1.997 was filed
on September 23, 2010 by the Public Patent Foundation.
Reexamination was ordered. Right of Appeal Notice (“RAN”) 2. The
Action Closing Prosecution was issued March 26, 2011. Id.
A second request for inter partes reexamination of the ’359
Patent was filed on June 15, 2012 by Bristol-Myers Squibb Co. Id.
Reexamination was ordered. Id.
The Reexamination proceedings were merged on January 17,
2013. Id. at 3. On November 25, 2013, the Action Closing
Prosecution was mailed.
Patent Owner appeals from the Examiner’s final rejection of
pending claims 1, 2, and 4–10.
An oral hearing took place on November 18, 2015 with only the
Patent Owner in attendance. A transcript of the hearing will be
entered into the record in due course. Neither of the Requesters
attended the hearing nor filed briefs in the Appeal.

II. RELATED CASES
Patent Owner lists four district court litigations and nine
reexamination proceedings said to be related to the present inter
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

3

partes reexamination. We have not been directed to a document in
these cases that is pertinent to the issues in this inter partes
reexamination.
III. REJECTIONS
The claimed subject matter of the ’359 Patent is directed to
amorphous ritonavir. Ritonavir is an inhibitor of HIV protease that
has been approved for use in the treatment of HIV. ’359 Patent, col.
1, ll. 30–45. The claims stand finally rejected by the Examiner as
follows:
1. Claims 1, 2, and 4–10 under 35 U.S.C. § 102(b) as
anticipated by or, in the alternative, under 35 U.S.C § 103(a) as
obvious over Martin Abstract,
1
as evidenced by Kempf I,
2
Norbeck,
3

and the Martin Poster.
4

2. Claims 1, 2, and 4–10 under 35 U.S.C. § 102(b) as
anticipated by or, in the alternative, under 35 U.S.C § 103(a) as

1 Martin D. et al., Method of Preparing an Orally Bioavailable Solid
Formulation of an Insoluble Protease Inhibitor as a Coprecipitate
with PVP and other Excipients, 13(9):S351 Pharmaceutical and
Analytical 7474 (1996).
2
Kempf I et al., ABT-538 is a potent inhibitor of human
immunodeficiency virus protease and has high oral bioavailability in
humans, 92 Pro. Natl. Acad. Sci. USA 2484–2488 (1995).
3
Norbeck et al., WO 97/01349, published January 12, 1997.
4 Martin et al., Method of Preparing an Orally Bioavailable Solid
Formulation of an Insoluble Protease Inhibitor as a Coprecipitate
with PVP and other Excipients, Abbott Poster (1996).

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

4

obvious over Dias Abstract, as evidenced by Kempf I, Norbeck and
the Dias Poster.
5

3. Claims 1, 2, and 4–10 under 35 U.S.C. § 102(b) as
anticipated by the Dias Poster.
4. Claims 1, 2, and 4–10 under 35 U.S.C. § 102(b) as
anticipated by the Martin Poster.
Patent Owner provided three Declarations by Simon Bates,
Ph.D. to support their arguments. We refer to these as the First Bates
Declaration (Jan 16 [no year given]), Second Bates Declaration (April
30, 2012), and Third Bates Declaration (August 13, 2013). Dr. Bates
testified in his written Declaration that he has 10 years of experience
in the field of characterization of pharmaceutical formulations. First
Bates Decl. ¶ 1. He is also stated that he has advised clients on
amorphous materials for pharmaceutical formulations and overseen
research relating to amorphous materials. Id. at ¶ 2. Based on his
experience and education, we find that Dr. Bates is qualified to testify
on the matters in his Declarations.

Summary
We reverse grounds 1 and 2. The rejections are based on
abstracts of the cited Dias and Martin Posters. The abstracts do not
contain the complete information and data which is disclosed in the

5
Dias et al., Physical and Oral Dog Bioavailability Evaluation of
ABT-538: PVP Co-Precipitates, l3 (9) S351 Pharmaceutical Research
7475 (1996). The pages of the Dias Poster are unnumbered. For
reference, we have numbered them 1 to 4.
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

5

posters. After reviewing the abstracts, we find that they do not fully
support the anticipation or obviousness rejection as articulated by the
Examiner. RAN 10, 12. In addition, the Examiner did not adequately
articulate a basis for determining that the claimed subject matter
would have been obvious to one of ordinary skill in the art based on
the abstracts.
We do not reach ground 4 (based on the Martin Poster). As
discussed at the oral hearing, ground 4 is weaker than ground 3 and
essentially reiterates ground 3 (based on the Dias Poster) which is
addressed in detail below.
The rejection of claims 1, 2, and 8–10 as anticipated by the
Dias Poster is reversed (ground 3).
The rejection of claims 4–7 as anticipated by the Dias Poster is
affirmed (ground 3).
IV. CLAIMS
The following claims are illustrative of the claimed subject
matter:
1. Substantially pure amorphous ritonavir.
4. A composition comprising amorphous ritonavir,
wherein said amorphous ritonavir is substantially pure.
6. A composition comprising amorphous ritonavir,
wherein greater than about 95% of ritonavir in said
composition is amorphous ritonavir.

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

6

V. CLAIM INTERPRETATION
We begin with claim interpretation because before a claim can
be compared to the prior art, the words and scope of the claim must be
properly interpreted.
During reexamination of an unexpired patent, claims are given
their broadest reasonable interpretation consistent with the patent
specification. In re Suitco Surface, Inc., 603 F.3d 1255, 1259 (Fed.
Cir. 2010); In re Abbott Diabetes Care Inc., 696 F.3d 1142, 1148
(Fed. Cir. 2012).

Amorphous ritonavir
Claims 1, 2, and 8–10 are each directed to “substantially pure
amorphous ritonavir.” We first turn to the patent specification to
determine whether it provides guidance as to the meaning of
“substantially pure.”
6
The ’359 Patent provides an express definition
of “substantially pure.”
As used herein, the term “substantially pure”, when used
in reference to amorphous ritonavir, refers to amorphous
ritonavir which is greater than about 90% pure. This
means that the amorphous ritonavir does not contain
more than about 10% of any other compound and, in

6
“The PTO applies to the verbiage of the proposed claims the
broadest reasonable meaning of the words in their ordinary usage as
they would be understood by one of ordinary skill in the art, taking
into account whatever enlightenment by way of definitions or
otherwise that may be afforded by the written description contained in
applicant’s specification.” In re Morris, 127 F.3d 1048, 1054 (Fed.
Cir. 1997).
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

7

particular, does not contain more than about 10% of any
other form of ritonavir.
’359 Patent, col. 9, l. 64 to col. 10, l. 3.
We adopt this definition of “substantially pure” because it has
been set forth with reasonable clarity and precision, providing explicit
notice of its meaning.
7
Thus, substantially pure amorphous ritonavir
can contain about 10% of other compounds, including the crystalline
form of ritonavir. This definition is consistent with the methods of
preparing amorphous ritonavir described in the ’359 Patent, which
including preparing “substantially pure amorphous ritonavir” by
melting crystalline Form I (’359 Patent, col. 3, ll. 36–39), adding a
solution of crystalline Form I in a solvent to an anti-solvent (id. at col.
3, ll. 40–61), adding a solution of crystalline Form I to water (id. at
col. 3, ll. 62–67, and lyophilization of a solution of ritonavir Form I
(id. at col. 4, ll. 5–8). See also Example 1 (id. at col. 5, ll. 30–40),
Example 6, and Example 7 (id. at col. 8, ll. 13–36). In each case, the
amorphous ritonavir is produced and isolated from the solvent as a

7
“Although an inventor is indeed free to define the specific terms
used to describe his or her invention, this must be done with
reasonable clarity, deliberateness, and precision. ‘Where an inventor
chooses to be his own lexicographer and to give terms uncommon
meanings, he must set out his uncommon definition in some manner
within the patent disclosure so as to give one of ordinary skill in the
art notice of the change.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
1994); “[P]atentees can act as their own lexicographers if they
‘clearly set forth a definition of the disputed claim term’ other than its
plain and ordinary meaning.” Thorner v. Sony Computer Entm’t Am.,
LLC, 669 F.3d 1362, 1365 (Fed. Cir. 2012).
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

8

“solid” in the amorphous form. Id. at col. 3, ll. 39, 49–50, 60–61; col.
4, ll. 3–4.
The term “amorphous ritonavir” is also recited in the claims.
“Amorphous” is a solid phase or state which is distinguished from the
crystalline state:
The three-dimensional long-range order that
normally exists in a crystalline material does not exist in
the amorphous state, and the position of molecules
relative to one another is more random as in the liquid
state. Typically amorphous solids exhibit short-range
order over a few molecular dimensions and have physical
properties quite different from those of their
corresponding crystalline states.
Hancock,
8
p. 1, col. 2.
Thus, we interpret the claim to be directed to the amorphous
form of ritonavir where it has the state as defined in Hancock.

Claims 4–7
Claims 4–7 each are drawn to a “composition comprising
amorphous ritonavir.” The ’359 Patent does not define the term
“composition.” We therefore adopt its ordinary meaning as found in a
general purpose dictionary to be “a product of mixing or combining
various elements or ingredients.”
9

8
Hancock et al., Characteristics and Significance of the Amorphous
State in Pharmaceutical Systems, 86 No.1, Journal of Pharmaceutical
Sciences 1–12 (1997).
9
http://www.merriam-webster.com/dictionary/composition
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

9

Amorphous versus composition
While amorphous ritonavir can contain other compounds,
including ritonavir in crystalline form, amorphous ritonavir is not a
composition because it is phase or state of matter unlike a
composition which is a combination of elements or ingredients. See
Hancock as reproduced above.

VI. ANTICIPATION BY DIAS POSTER
Claims 1, 2, and 8–10
Claims 1, 2, and 8–10 are directed to substantially pure
amorphous ritonavir. We have interpreted the claims to read on
ritonavir in the amorphous form. Dias Poster (hereinafter “Dias”)
describes a composition that is a co-precipitate of PVP
(polyvinypyrillodone) and ABT-538. Dias, p. 1, Abstract. ABT-538
is ritonavir. RAN 10. The amorphous form is a state of matter and
not a composition. See “Claim Interpretation” section V. above.
Since Dias describes the amorphous ritonavir in the form of a
composition, we reverse the anticipation rejection of claims 1, 2, and
8–10.

Claims 4–7
Claims 4–7 are drawn to compositions which comprise
substantially pure amorphous.
The Examiner rejected the claims over the disclosure in Dias of
a co-precipitate of ritonavir and PVP. Dias describes co-precipitating
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

10

PVP and ritonavir in an effort to improve the drug’s bioavailability.
Dias, p. 1, Abstract. Dias states that the co-precipitates maintained
the drug in the amorphous state. Id.
The issue in the rejection is whether Dias describes the presence
of substantially pure amorphous ritonavir in the composition of PVP:
ritonavir, where the amorphous ritonavir does not contain more than
10% of other compounds. We begin with identifying the pertinent
facts (findings of fact or “FF”) in Dias necessary to determine whether
the claimed subject matter is anticipated.

Findings of Fact
FF1.
Polyvinylpyrillodone (PVP) has been used to form
co-precipitates of an insoluble antiviral compound, ABT-
538 [ritonavir], in an effort to increase bioavailability of
this drug. PVP:drug co-precipitates were prepared using
a solvent evaporation method. Two techniques were
used to prepare the PVP:drug coprecipitates namely
spray drying and layering onto suitable substrates.
Several ratios of drug to PVP and various molecular
weight grades of PVP were evaluated in this study using
differential scanning calorimetry and X-ray powder
diffraction. Preliminary studies indicate that the co-
precipitates maintained the drug in an amorphous form
which were stable at 80°C and at ambient room
temperature/75% RH conditions for two weeks.
Dias, Abstract.
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

11

FF2.
OBJECTIVE
To evaluate feasibility of forming PVP co-precipitates of
ABT-538, to render ABT-538 in an amorphous form with
the goal of improving the bioavailability of ABT-538, a
poorly soluble, high dose antiviral agent.
Id. at p. 1.
FF3.
I. Drug PVP coprecipitates prepared by slow evaporation
Various drug:PVP ratios were prepared as shown in
Table 1. The purpose of this was to determine the
optimum ratio of drug to PVP in order to achieve the
amorphous form of drug as well as to characterize the
intrinsic dissolution properties of the co-precipitate.
Id. at p. 2, col. 1.
FF4.
Thermal analysis [by differential scanning calorimetry
(DSC)] of the PVP K30 precipitates are shown in Figure
1. From these results it may be noted that a drug melting
peak is observed in a 3:1::drug:PVP ratio. This drug
melting peak was not observed in the 1:1 and 1:3 PVP
K30 co-precipitate ratios indicating that the drug exist in
the amorphous form for coprecipitates where ther[e] is
more than 50% of PVP K30.
Id.
FF5.
Thermal analysis of all the PVP K90 co-precipitates
tested also did not show a drug melting peak indicating
that the drug exists in the desired amorphous form.
Id.
FF6.
II. PVP drug co-precipitate formation using spray drying
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

12

. . .
Physical Evaluation
X-ray diffraction patterns for these spray dried
formulations are shown in Figure 3. These patterns show
that the drug exists in amorphous form which was
expected from the solvent evaporation technique.
Id. at p. 3, col. 1.
FF7.
Physical Evaluation
X-ray diffraction patterns obtained using the PVP co-
precipitate layered colloidal silicon dioxide are shown in
Figure 4.
From Figure 4 it can be seen that ABT-538 is present in
an amorphous state in the drug PVP co-precipitate
layered silicon dioxide.
Id. at p. 3, col. 2.
FF8.
The 1:1 drug PVP co-precipitate layered on silicon
dioxide was placed on a 2 week stability evaluation . . .
Physical stability with respect amorphous ABT-538
reverting to crystalline ABT-538 was determined by X-
ray diffraction. . . .
Results, shown in Figure 5, indicate that ABT-538
maintained its amorphous nature under the conditions
studied.
Id.
Discussion
Claims 4–7 (composition claims)
The Examiner found that Dias expressly characterized ABT-
538 (ritonavir) as being present in the co-precipitates in an amorphous
form, meeting the claims of claims 4–7 of “amorphous ritonavir.”
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

13

RAN 12. See FF1–FF8. With respect to the requirement that the
claims have no more than about 10% of any other compound, the
Examiner found that Dias stated that under storage conditions, as
assessed by x-ray powder diffraction, there was no conversion to other
polymorphic forms, indicating that no crystalline ritonavir is present.
RAN 13, 20; FF8.

1. Amorphous ritonavir
Patent Owner contends that amorphous ritonavir is not present
in Dias’s co-precipitate because the endotherm at the melting point of
amorphous ritonavir was not observed. Appeal Br. 19–20. To
support this position, Patent Owner cites testimony from Dr. Bates
Third Declaration.
Patent Owner’s argument is not supported by a preponderance
of the evidence. First, Dias expressly states in several places
throughout the poster that amorphous ritonavir was produced. FF1,
FF4–FF8. Despite the absence of the melting point endotherm, Dias
still concluded that the amorphous form was present. Patent Owner
has not provided evidence to doubt the credibility of Dias. Second,
Dr. Bates acknowledged that amorphous ritonavir was produced by
Dias:
Further, in my opinion, the co-precipitated products of
Martin and Dias contain regions of amorphous ritonavir
(see, paragraph 14) and these regions would not have
been understood or expected by a person having ordinary
skill in the art in July 1998 to be “substantially pure” as
that term is used in the ’359 Patent. First, a person
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

14

having ordinary skill in the art in July 1998 would have
expected the presence of residual solvent in the regions
of amorphous ritonavir in the co-precipitated product of
Martin and Dias, and therefore that the regions of
amorphous ritonavir were not substantially pure.
Second Bates Declaration ¶ 17.
Dr. Bates discussion on the absence of the glass transition
temperature (Tg) for ritonavir as casting doubt on the presence
substantially pure ritonavir (Third Bates Declaration ¶ 18) has little
merit in view of his explicit admission that amorphous ritonavir is
present.

2. Substantially pure ritonavir
A. Presence of crystalline forms
The Examiner’s basis for finding that crystalline ritonavir is not
present in more than an amount of about 10% in the amorphous
ritonavir described in Dias is principally based on Dias’s storage
experiment. In this experiment, Dias reported that the “Results,
shown in Figure 5, indicate that ABT-538 maintained its amorphous
nature under the conditions studied.” FF8. This determination was
made by x-ray diffraction where the authors stated that physical
stability assessed by determining whether “amorphous ABT-538 [is]
reverting to crystalline ABT-538.” Id. In other words, the authors
looked for the presence of crystalline ABT-538, but did not report it.
Dr. Bates testified the Dias is “reporting the physical stability of
the co-precipitated product, and not the ritonavir contained within the
co-precipitated product.” Second Bates Declaration ¶ 16. This
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

15

statement is not supported by sufficient evidence. As indicated above,
Dias expressly refers to the reversion of the amorphous form to the
crystalline form (FF8), providing evidence that Dias is in fact looking
at the stability of the amorphous form and asking whether it reverts to
the crystalline form. Dias does not identify the presence of the
crystalline form in the x-ray diffraction data, indicating confidence in
his data.

B. Substantially pure
Claim 4, by definition of “substantially pure,” requires the
presence of less than 10% of other compounds in the amorphous
ritonavir, i.e., about 90% or more of the ritonavir is amorphous.
Claim 6 require that 95% of the ritonavir is amorphous and claim 7
requires that amorphous ritonavir constitutes 97% of the composition.
There are several sources for the 10% or less of other compounds:
crystalline ritonavir, solvents, and other additives.

(1) Presence of crystalline ritonavir
With respect to the presence of 10% or less of crystalline
ritonavir, the Examiner’s basis, again, is the stability data described in
FF8. In simple terms, Dias conducts x-ray diffraction which should
detect the presence of crystalline ritonavir, but Dias does not report
that the crystalline form was detected.
Patent Owner argues crystalline ritonavir would not have been
detected in Dias’s co-precipitate at the levels of ritonavir present.
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

16

Appeal Br. 23–25. While Dr. Bates provided testimony on Dias, we
have not been directed to where in his declaration he commented on
the level of detection argument. Patent Owner’s support for the
argument comes from Hancock which has the following disclosure:
As there is no long-range three-dimensional
molecular order associated with the amorphous state, the
diffraction of electromagnetic radiation (e.g., X-rays) is
irregular compared to that in the crystalline state (Figure
4). Diffraction techniques are perhaps the most definitive
method of detecting and quantifying molecular order in
any system . . . Conventional X-ray powder diffraction
measurements can be used to quantify non-crystalline
material down to levels of about 5% [footnote omitted]
and with temperature and environmental control can also
be used to follow the kinetics of phase transformations,
or to quantify the presence of a crystalline drug in an
amorphous excipient matrix [footnote omitted].
Hancock 5.
This passage is not precisely on point because it refers to the
detection of “non-crystalline material,” i.e., the amorphous state,
down to levels of 5% in a material apparently comprising crystalline
material, while the experiments in Dias were apparently to detect
small amounts of crystalline ritonavir in material largely made of
amorphous ritonavir.
Nonetheless, Hancock characterizes x-ray diffraction as
“perhaps the most definitive method of detecting and quantifying
molecular order in any system.” Hancock also states that it can be
used to “quantify the presence of a crystalline drug in an amorphous
excipient matrix.” Id. Consistent with Hancock’s statements, the
Dias authors utilized the technique to detect crystalline ritonavir in
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

17

amorphous ritonavir and concluded that the amorphous form of
ritonavir was stable and that it did not revert to the crystalline form.
FF8. We credit this evidence over the declaration evidence.
Figure 4 shows x-ray diffraction data on crystalline drug
(“100% ABT-538”) and amorphous ritonavir. Figure 5 shows
ritonavir: PVP stored under stressed conditions. FF8. Dias did not
note the presence of ordered crystalline ritonavir in the samples tested.
Thus, while Patent Owner – without expert testimony – asserted that
the levels of ritonavir would have been too low to detect crystalline
ritonavir (Appeal Br. 23), the Dias authors clearly did not believe this
to be the case because they used x-ray powder diffraction to look for
the reversion of amorphous ritonavir to the crystalline form during the
2 week trial and reported none. Dias therefore used x-ray diffraction
in the same way described in Hancock.
Patent Owner states:
Therefore, even if the ritonavir mixture contained less
than 10% of non-amorphous ritonavir, a person having
ordinary skill in the art in July 1998 would have
understood that the known limits of detection of PXRD
[powder x-ray diffraction] would not be able to confirm
the amounts of non-amorphous ritonavir in the ritonavir
coprecipitates of the Dias Poster.
Id. at 23.
Patent Owner does not have adequate factual support for this
statement. As explained above, Dias used the technique to detect
crystalline drug in amorphous drug, and did not find any that reverted
over the two week period. We consider the Dias authors to be at least
of ordinary skill in the art, and thus contrary to Patent Owner’s
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

18

unsupported statements that the ordinary skilled worker would have
understood the levels of the crystalline form to be outside of the
detection levels of x-ray diffraction, the Dias authors used it for that
very purpose.

(2) Presence of solvent
Dr. Bates contends that the ritonavir described in Dias is not
“substantially pure” because “a person having ordinary skill in the art
in July 1998 would have expected the presence of residual solvent in
the regions of amorphous ritonavir in the co-precipitates of . . .
[Dias].” Third Bates Declaration ¶ 12. Dr. Bates also stated that Dias
“notes that its co-precipitate is formed by solvent evaporation. The
presence of residual solvent may act as a plasticizer for the ritonavir
thereby inducing crystallization. This would render the ritonavir not
substantially pure as recited in the claims of the ’359 Patent.” Id. See
also ¶¶ 24–25 discussing Yoshioka. Furthermore, Dr. Bates testified
that the drying process in Dias was not controlled. Id. at ¶ 22.
Dr. Bates testimony is not supported by adequate factual
underpinnings. Dr. Bates does not explain why the “slow
evaporation” utilized in Dias (at p. 2, col. 1) would not eliminate all
the solvent. Dr. Bates states that residual solvent may induce
crystallization and stability, but the stability experiments did not show
reversion of amorphous ritonavir into the crystalline form,
undermining Dr. Bate’s rationale that instability-inducing residual
solvent is present.
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

19

(3) Differential scanning calorimetry (“DSC”)
Dr. Bates argues that the DSC performed in Dias is qualitative
(Third Bates Declaration ¶ 13), no Tg for amorphous ritonavir was
observed (id. at ¶ ¶ 17–18), and thus the DSC cannot be used to
determine whether substantially pure amorphous ritonavir is present
(id. at ¶ ¶ 18–20). Dr. Bates also testified that the substrates on which
the ritonavir was deposited “will impact the amorphous ritonavir.” Id.
at ¶ 16. Dr. Bates discussed problems with interpreting the data using
DSC. Id. at ¶ 20.
It is not necessary to rely on the DSC data in finding that the
amorphous ritonavir was substantially pure, because the Examiner
also found that the x-ray diffraction stability test provided evidence of
its purity. RAN 13–14, 20. We have discussed this issue above, and
remain unpersuaded by Dr. Bates’ testimony. See Section B(1).

(4) Tg (glass transition temperature of amorphous
ritonavir)
Dr. Bates and Patent Owner have conjectured that the absence
of the Tg of substantially pure amorphous ritonavir indicates that it is
not present. However, as already discussed, Dr. Bates acknowledged
that amorphous ritonavir is present. Second Bates Declaration ¶ 17.

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

20

(4) Conditions
Patent also argues that Dias is deficient because the authors did
not disclose certain conditions used to make the amorphous ritonavir.
Dr. Bates testified:
Dias do not disclose the conditions under which the co-
precipitates therein were created, and also include
language indicating that even were the conditions therein
reproduced, there would not be a reasonable likelihood
that “substantially pure” amorphous ritonavir would be
obtained. . . Dias [is] silent with respect to how the co-
precipitates therein were formed. They do not disclose,
for example, the appropriate temperature range (to avoid
degradation), solvent combinations and amounts (to
avoid physical instability and recrystallization of an API
out of its amorphous state), and design variables (such as
drying conditions, necessary to remove excess solvent)
necessary to make “substantially pure” amorphous
ritonavir, as that term is used in the ’359 Patent. In
particular, Martin and Dias fail to disclose or suggest
how the solvents in the co-precipitates therein are
removed.
Second Bates Decl. ¶ 21.
Page 2 of Dias describes a procedure for producing the co-
precipitate of PVP and ritonavir. While the different ratios of PVP to
ritonavir are described in Table 1 of Dias, not all the experimental
conditions used to make the co-precipitate are completely described.
However, consistent with the Examiner’s finding that the co-
precipitation method was known in the art at the time of the invention
(RAN 23), Dias indicates that the methods utilized were conventional:
Thus, two methods of improving bioavailability of a high
dose poorly soluble drug are:
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

21

• increase solubility by changing solid state from
crystalline to amorphous
• increase dissolution rates by increasing solubility . . .
Both these can be achieved by forming a solid co-
precipitate of the drug in a hydrophilic carrier like of
polyvinyl pyrillidone (PVP) to generate solid
solution/dispersion. Over the years there have been
many reports on the use of PVP to generate solid
solution/dispersion. The solvent evaporation method was
used in preference to the melt method since the drug was
thermolabile and exposing the drug to the high
temperatures in the melt method could be detrimental to
drug stability.
Dias, p. 1, col. 2.
Yoshioka,
10
published in 1995, describes the co-precipitation of
PVP and a drug to form amorphous drug, providing evidence that the
method was known in the art at the time of the invention. Yoshioka
specifically states:
The use of polymers and other glass-forming
solids to form amorphous pharmaceutical mixtures has
been widely reported in the context of enhancing the
rates of dissolution and bioavailability of drugs with low
water solubility. Typically the ratio of polymer to drug
used to enhance dissolution rates is rather high, (e.g., 4:1
or greater). Previous studies with indomethacin-poly
(vinylpyrrolidone) coprecipitates have shown that PVP
used for this purpose does act as an inhibitor of
crystallization.
Yoshioka 983 (col. 2) (footnotes omitted).

10
Yoshioka et al., Inhibition of lndomethacin Crystallization in Poly
(vinylpyrrolidone) Coprecipitates, 84 No. 8, Journal of
Pharmaceutical Sciences 983–986 (1995).
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

22

Consequently, the preponderance of the evidence in this record
does not support Patent Owner’s contention that Dias is not enabled to
make substantially pure ritonavir since such methods were known in
the art as established by Dias and Yoshioka.

(5) Ambiguity of precipitate formed
Patent Owner contends that there is ambiguity surrounding the
nature of the co-precipitates prepared. Appeal Br. 21. Dias tested two
forms of PVP, a K30 grade and a K90 grade. Patent Owner discusses
the dissolution data of the two PVP forms as summarized in Table 1
of Dias, commenting that contrary to the results, one would have
expected that the PVP K30 co-precipitate would have a higher
dissolution than the more viscous PVP K90 co-precipitate at the 1:1
ratio of drug to PVP. Id. Patent Owner states that the “coprecipitates
are not exhibiting the expected normalized intrinsic dissolution
relationship and it appears the PVP and the ritonavir may be
interacting in some manner to impact these results.” Id. Patent
Owner did not identify testimony on this issue by Dr. Bates.
Patent Owner’s argument is not persuasive. First, Patent Owner
did not provide evidence that PVP K30 would have been expected to
have a higher dissolution rate than the PVP K90 grade. Second, Dias
commented on the behavior of the PVP K90 co-precipitate, stating
that “it behaved differently than the PVP K30 grade in that the
intrinsic dissolution rate increased then dropped.” Dias, p. 3, col. 1.
Dias said the drop off “could be explained” by the formation of a
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

23

viscous pellet surfaces on contact with water retarding the dissolution
rate. Id. Thus, Dias noted the behavior of the PVP K90 and did not
comment that it was unusual because it had higher dissolution rate
than PVP K30.
With respect the argument that the ritonavir and PVP are
“interacting in some manner” to impact the dissolution results (Appeal
Br. 21), we observe that it was known prior to the invention that PVP
can inhibit drug crystallization so an “interaction” of some kind is
entirely expected. Yoshioka 983 (see quoted passage above; also at
986 (col. 2): “The use of PVP in amorphous dry coprecipitates with
indomethacin significantly inhibits indomethacin crystallization at
levels as low as 5% PVP and at temperatures as high as 70°C.”)

(6) About 90% or more of amorphous ritonovir
Claim 4 requires at least 90% of amorphous ritonavir. Claims
5–7 recite specific amounts of amorphous ritonavir, namely, 90%,
95%, and 97%, respectively. In other words, in claims 4 and 5 up to
about 10% of other compounds, including crystalline ritonavir, can be
present in the amorphous ritonavir; and up to about 5% in claim 6 and
3% in claim 7.
Patent Owner contends that the Examiner has not established
that Dias’s co-precipitate comprise amorphous ritonavir in the recited
amounts. Appeal Br. 30.
The Examiner’s basis for finding that Dias’s co-precipitate
meets the required quantities is the x-ray diffraction data of Figs. 4
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

24

and 5. RAN 12–13; FF8. This evidence indicates that crystalline
ritonavir is not present since Dias stated that reversion to the
crystalline form was determined and the results showed it “maintained
its amorphous nature.” FF8. As to the solvent, Examiner had a
reasonable basis to believe that such requirement was met based on
the solvent evaporation technique utilized to remove solvent from the
co-precipitate. FF3. As mentioned, Dr. Bates mentioned that the
solvent can cause crystals to form; however, Dias did not report
crystal formation consistent with the absence of solvent. FF8.
Because inter partes reexamination is conducted under the
same procedural rules as regular patent application prosecution, the
allocation of burdens is similar. See 37 C.F.R. §1.937(b) “(b) The
inter partes reexamination proceeding will be conducted in accordance
with §§ 1.104 through 1.116, the sections governing the application
examination process.”) Thus, the Examiner provided evidence that
the numerical limitations of claims 4–7 were met. In re Oetiker, 977
F.2d 1443, 1445 (Fed. Cir. 1992). Patent Owner came forward with
rebuttal arguments and evidence, such as the First, Second, and Third
Bates Declarations. In considering the entirety of the evidence before
us, including the Declarations and the Hancock publication, we
conclude that a preponderance of the evidence supports the conclusion
that Dias describes a composition with about 90% or more, 95% or
more, and 97% or more of amorphous ritonavir.

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

25

SUMMARY
The issue in the rejection over Dias is whether a preponderance
of the evidence supports the Examiner’s finding that Dias anticipates
the compositions claims comprising substantially pure amorphous
ritonavir. The Examiner found that amorphous ritonavir is described
in Dias based on Dias’s explicit and repeated statements that
amorphous ritonavir is formed when co-precipitated with PVP. While
Patent Owner appears to challenge that amorphous ritonavir is formed
in the co-precipitates because the glass transition temperature of the
amorphous form was not observed, its own expert admits that
amorphous ritonavir is present.
While there is express disclosure about the presence of
amorphous ritonavir in the co-precipitate with PVP, there is no
explicit teaching that the amorphous form is present in amounts of at
least about 90%, 95%, and 97% as required by the claims. The
Examiner’s principal basis for finding that these values are anticipated
by Dias is Dias’s teaching that the amorphous ritonavir is stable and
does not revert to the crystalline form. The Examiner cited the x-ray
diffraction patterns shown in Figs. 4 and 5 of Dias to support this
finding.
Patent Owner argues that the x-ray diffraction data is not
quantitative, the ritonavir is at levels below which the crystalline form
could be detected, solvent is present, and the conditions to make the
amorphous ritonavir are not fully disclosed. We find that the evidence
is inadequate to support these contentions.
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

26

Specifically, the Dias authors utilized x-ray diffraction to
determine whether crystalline ritonavir was present in their stored
samples, providing evidence that at least one of ordinary skill in the
art would have believed that the method was capable of detecting the
crystalline form had it been present.
Patent Owner’s expert opined that solvent may be present and
that such solvent could lead to crystallization of the ritonavir.
However, Patent Owner’s expert did not provide a strong factual basis
to establish the presence of solvent in the co-precipitate. Dias
reported that the amorphous form was stable, and did not revert to the
crystalline form, undermining the argument that instability-inducing
solvent was present.
As to the contention that Dias is not enabling, the Examiner
found that co-precipitation with PVP was well-known prior to the
filing date of the patent, a finding supported by the cited Yoshioka
publication and Dias, itself.
For the foregoing reasons, the rejection of claims 4–7 as
anticipated by the Dias Poster is affirmed.

VII. TIME PERIOD FOR RESPONSE
In accordance with 37 C.F.R. § 41.79(a) (1), the “[p]arties to
the appeal may file a request for rehearing of the decision within one
month of the date of: . . . [t]he original decision of the Board under
§ 41.77(a).” A request for rehearing must be in compliance with
37 C.F.R. § 41.79(b). Comments in opposition to the request and
additional requests for rehearing must be in accordance with
37 C.F.R. § 41.79(c) & (d), respectively. Under 37 C.F.R. § 41.79(e),
the times for requesting rehearing under paragraph (a) of this section,
Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

27

for requesting further rehearing under paragraph (d) of this section,
and for submitting comments under paragraph (c) of this section may
not be extended.
An appeal to the United States Court of Appeals for the Federal
Circuit under 35 U.S.C. §§ 141–144 and 315 and 37 C.F.R. § 1.983
for an inter partes reexamination proceeding “commenced” on or
after November 2, 2002 may not be taken “until all parties’ rights to
request rehearing have been exhausted, at which time the decision of
the Board is final and appealable by any party to the appeal to the
Board.” 37 C.F.R. § 41.81. See also MPEP § 2682 (8th ed., Rev. 7,
July 2008).
In the event neither party files a request for rehearing within the
time provided in 37 C.F.R. § 41.79, and this decision becomes final
and appealable under 37 C.F.R. § 41.81, a party seeking judicial
review must timely serve notice on the Director of the United States
Patent and Trademark Office. See 37 C.F.R. §§ 90.1 and 1.983.
No time period for taking any subsequent action in connection
with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED

Appeal 2015-006298
Reexamination Control 95/000,570 & 95/002,019
Patent 7,148,359 B2

28

For Patent Owner:

ABBOTT LABORATORIES
100 ABBOTT PARK RD
D377/AP6A-1
ABBOTT PARK, IL 60064

For Third Party Requestor:

PUBLIC PATENT FOUNDATION
55 FIFTH AVENUE, SUITE 928
NEW YORK, NY 10003

and

MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
BRISTOL-MYERS SQUIBB
300 SOUTH WACKER DRIVE
CHICAGO, IL 60606