Ex Parte Gilljam et al

Patent Trial and Appeal Board

Oct 9, 2018

13638234 (P.T.A.B. Oct. 9, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/638,234 12/12/2012 Gustav Gilljam
26694 7590 10/11/2018
VENABLELLP
P.O. BOX 34385
WASHINGTON, DC 20043-9998
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
37385-401524 9098
EXAMINER
TSAY,MARSHAM
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
10/11/2018 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
PTOMail@Venable.com
khauser@venable.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GUSTAV GILLIAM and STEFAN WINGE 1
Appeal2017-009463
Application 13/63 8,234
Technology Center 1600
Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and
RYAN H. FLAX, Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision under 35 U.S.C. § 134(a) involving claims directed
to manufacturing a vitamin K dependent protein in a purification sequence
employing chromatography. Claims 1, 3-18, 20-22, and 24 are on appeal as
rejected under 35 U.S.C. § 103.2 We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.
1 Appellants identify the Real Party in Interest as "Octapharma AG."
Appeal Br. 1. Herein we reference the Specification of Sept. 28, 2012
("Spec."); Final Office Action of Apr. 14, 2016 ("Final Action"); Appeal
Brief of Jan. 10, 2017 ("Appeal Br."); Examiner's Answer of May 4, 2017
("Answer"); and Reply Brief of June 30, 2017 ("Reply Br.").
2 We understand any rejection under 35 U.S.C. § 112, first paragraph, for
lack of enablement to be withdrawn. See Answer 2 ("The following
ground(s) or rejection are applicable to the appealed claims," not followed
by any reference to an enablement rejection).
Appeal2017-009463
Application 13/638,234
STATEMENT OF THE CASE
The Specification states that the "invention pertains to a process of
purifying vitamin K dependent proteins such as coagulation factor IX
(abbreviated as FIX [also "F9" herein])." Spec. 1:4--5. The Specification
further states:
Hemophilia is a group of hereditary genetic disorders that impair
the body's ability to control blood clotting or coagulation. In one
of its forms, Hemophilia B, clotting factor IX (FIX) is deficient,
Hemophilia B occurs in about 1 in 25,000 male births. Factor IX
( or Christmas factor) is one of the serine proteases of the
coagulation system. It is a vitamin K-dependent plasma protein
that participates in the intrinsic pathway of blood coagulation by
converting factor X to its active form in the presence ofCa2+ ions,
phospholipids, and factor VIIIa. The FIX protein is an essential
factor in blood coagulation with multifunctional properties.
Id. at 1:8-15. The Background of the Specification also identifies a second
blood coagulation factor VIII, also called FVIII ( or "F8" herein). Id. at 3 :20
et sec. The Specification states, "WO-A-2009/007451 discloses a
purification method of FVIII using a mixed-mode or multimodal resin." Id.
at 3 :20-21. The Specification further states,
WO-A-2009/156430Al discloses a purification method ofFVIII
using a mixed-mode or multimodal resin. The purification
method is based on contacting FVIII protein in a solution having
a high ionic strength with a multimodal or mixed-mode resin
containing ligands which comprise a hydrophobic part and a
negatively charged part and eluting said FVIII protein with an
elution buffer comprising at least one amino acid which is
positively charged at pH 6-8.
Id. at 4:19-24; see also Borgvall. 3
3 US 8,329,871 B2 (issued Dec. 11, 2012) ("Borgvall") (Borgvall is the U.S.
counterpart of PCT Pub. No. W02009/156430). We note Borgvall has the
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Application 13/638,234
The Background of the Specification also states:
Multimodal ( or mixed mode) chromatography is a tool for
purifying proteins. Described in, for example, Manufacturer data
sheet GE Healthcare (11-0035-45AA) Capto Adhere,
Manufacturer data sheet GE Healthcare (28-9078-88AA) Capto
MMC and WO-A-2009/024620 "A process for the isolation and
purification of a target protein, free of prion proteins".
Spec. 5:18-22; 4 see also id. 12:16-25 (describing these GE Healthcare
disclosures, along with the use of a neutral pH range and increased salt
concentration for stability as described in "EP-A-1 707 634"). 5
Independent claim 1 is representative and is reproduced below:
1. A process of manufacturing a Vitamin K dependent
Protein in a purification sequence employing chromatography
compnsmg
- providing a fraction containing a Vitamin K dependent Protein
in an aqueous solution;
- contacting the fraction containing the Vitamin K dependent
Protein with a multimodal resin at a pH between 6-9; and
- eluting the Vitamin K dependent Protein from the multimodal
resin at a pH between 6 to 9 in a buffer comprising arginine,
wherein the Vitamin K dependent Protein is plasma
derived FIX (Factor IX) or recombinantly produced FIX.
same assignee/owner as the appealed application and overlapping
inventorship.
4 WO-A-2009/024620 refers to International Patent Application Pub. No.
WO 2009/024620 A2, published Feb. 26, 2009 ("WO '620"). We note
WO '620 has the same assignee/owner as the appealed application and
overlapping inventorship.
5 EP-A-1 707 634 refers to EP 1 707 634 Al, published Oct. 4, 2006
("EP '634"). We note EP '634 has the same assignee/owner as the appealed
application and overlapping inventorship.
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Application 13/638,234
Appeal Br. 31 (Claims Appendix).
The following rejections are appealed:
Claims 1, 3-11, 17, 18, 20-22, and 24 stand rejected under 35 U.S.C.
§ I03(a) over Borgvall and Butenas,6 as evidenced by Morfini. 7
Claims 12-16 stand rejected under 35 U.S.C. § I03(a) over Borgvall
Butenas, Adams, 8 Foster,9 Bumouf, 10 and Roberts, 11 as evidenced by
Morfini.
DISCUSSION
"[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting aprimafacie case ofunpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Arguments made by Appellants in the Appeal Brief and properly presented
in the Reply Brief have been considered in this Decision; arguments not so-
presented in the Briefs are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2015);
see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010)
6 S. Butenas and K. G. Mann, Blood Coagulation, 67(1) BIOCHEM. 3-12
(2002) ("Butenas").
7 Massimo Morfini et al., Clinical use of factor VIII and factor IX
concentrates, 1 l(Supp. 4) BLOOD TRANSFUS. s55-s63 (2013) ("Morfini").
8 US 6,624,295 B 1 (issued Sept. 23, 2003) ("Adams").
9 US 6,627,737 Bl (issued Sept. 30, 2003) ("Foster").
10 T. Bumouf and M. Radosevich, Nanofiltration of plasma-derived
biopharmaceutical products, 9 HAEMOPHILIA 24--37 (2003) ("Bumouf').
11 Peter L. Roberts, Virus inactivation by solvent/detergent treatment using
Triton X-100 in a high purity factor VIII, 36 BIOLOGICALS 330-35 (2008)
("Roberts").
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Application 13/638,234
(informative) ("Any bases for asserting error, whether factual or legal, that
are not raised in the principal brief are waived.").
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). "In determining
whether the subject matter of a patent claim is obvious, neither the particular
motivation nor the avowed purpose of the patentee controls. What matters is
the objective reach of the claim. If the claim extends to what is obvious, it is
invalid under§ 103." Id. at 419.
The Examiner determined the claims would have been obvious over
Borgvall, taking into consideration the knowledge of those of ordinary skill
in the art that processing techniques similar to Borgvall's F8 purification
steps would be useful in isolating F9, which is the other coagulation factor
of primary importance in treating hemophilia, as taught by Butenas and as
evidenced by Morfini. Final Action 7-17 and Answer 2---6, 11-22
(collectively citing Borgvall 3: 1---6:67; Butenas 3--4, 9; and Morfini s56-
s57). The Examiner also cited GE Healthcare Capto MMC data sheet 11-
0035-45AA, which is referenced in Borgvall (at 3:47-53) and in Appellants'
Specification (at 5:18-25 and 12:16-20). See Final Action 12. The
Examiner further found a reasonable expectation that Borgvall's purification
steps could be successfully applied to F9 because "the native environment of
both proteins comprises [similar] physiological conditions and it was known
that multimodal chromatography can be used to selectively purify different
proteins at neutral conditions." Id. at 14.
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We discern no error in the Examiner's determinations. We adopt the
Examiner's findings of fact and rationale in this Decision. Final Action 7-
17; Answer 2-22.
As noted by the Examiner, Borgvall teaches the entirety of the
claimed invention except that instead of the purified protein being F9, as
claimed, it focuses on purifying F8, which is a different clotting factor
protein, as discussed above. See Borgvall Abstract; see also Answer 4.
Regarding F8, Borgvall teaches providing the protein as a fraction having
the protein in aqueous solution (Borgvall 3:37-39), contacting this with a
multimodal resin, specifically disclosed as a resin manufactured by GE
Health Care (id. at 3:47-53 (citing GE Health Care data sheets 11-0035-
45AA and 28-9078-88AA)), at a pH of 6-8 (id. at 3:57--4:40), and eluting
the protein in an arginine-containing buffer at this pH (id. at 4:25-31 ).
Besides these similarities between the Borgvall disclosure and the
claimed invention and its description in the Specification, there are other
striking similarities. From the outset, both Borgvall and the Specification's
disclosure are focused on purifying one of two key proteins/ clotting factors,
the deficiency of which is responsible for hemophilia. The appealed
application's Specification cites much of the same background on
hemophilia and protein purification as does Borgvall, e.g., WO-A-
2009/007451, EP '634, WO-A-2005-082483, and WO-A-2005/121163.
Spec. 3--4; Borgvall col. 2. And, Appellants' Specification also describes
the invention of the appealed claims by citing to Borgvall's PCT counterpart
publication (WO-A-2009/156430 Al), and citing other common references
also cited in Borgvall (e.g., GE Healthcare (or Health Care) Manufacturer's
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data sheets 11-0035-45AA regarding Capto Adhere, 28-9078-88AA
regarding Capto MMC, EP '634 regarding using mild pH parameters in
multimodal chromatographic protein, e.g., F8 and F9, purification) to teach
the processes and components used to purify F9 as opposed to Borgvall' s
F8. See, e.g., Spec. 4, 5, 10, 12; Borgvall 3:47--4:2. None of this is
determinative on obviousness; however, it is supportive of the strong
relevance of Borgvall to the claimed invention (it is necessary to fully
explain the invention here) and the prior art's significance in the field to
those of skill in the art.
The question presented, and most strenuously argued by Appellants, is
whether it would have been obvious to use the Borgvall F8 purification
technique to purify F9, as claimed.
Appellants argue "[ t ]here is simply no structural similarity between
FVIII and FIX for reasons of record. Furthermore, the two proteins have
different functions -FVIII is a co-factor and FIX is a pro-enzyme. (See
Morfini s55)." Appeal Br. 14. Due to this dissimilarity between the two
proteins, Appellants argue there would have been no reasonable expectation
of successfully using the Borgvall techniques to purify F9. Id. Appellants
argue that "all proteins differ in their 'amino acid residues and [ ] amino acid
composition and carbohydrate composition."' Id. at 15 (source not cited).
Appellants contend "[ u ]nless there is a chemical similarity between the
proteins, there can be no reasonable expectation that a purification method
for any one protein would apply to any other protein. This is the case for
FVIII and FIX which differ dramatically in chemical composition and
properties." Id.
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Application 13/638,234
The differences, chemical and structural, between F8 and F9 that
Appellants contend cause unpredictability relating to methods of their
purification, includes the number of amino acid residues (more for F8), the
molecular weight (higher for F8), number of basic amino acid residues,
number of hydrophobic amino acid residues and those with hydroxyl side
chains, carbohydrate content (higher for F9), number of surface residues
(more for F8), surface area (larger for F8) and the percentage of negative
and hydrophobic surface residues (greater for F9), and whether the protein
binds to cationic exchange resin SP Sepharose FF (F8 does, F9 does not).
Appeal Br. 16-1 7.
Looking to Borgvall, we note it, and the Specification, state "[ m ]ulti
modal ( or mixed mode) chromatography is a tool for purifying proteins."
Borgvall 3:47--48 (emphasis added); Spec. 5:18. Each ofBorgvall and the
Specification then immediately identifies GE Healthcare' s Capto Adhere
and Capto MMC as suitable resin media for the process, also citing
WO '620 and EP '875 12 (which are at least related to one another, each
being entitled "A process for the isolation and purification of a target
protein, free of prion proteins" and sharing inventorship and ownership) as
also providing a relevant teaching for the process. See Borgvall 3:48-53;
Spec. 5: 19-22. We note that neither Borgvall nor the Specification mentions
that only certain proteins, having specific properties, can be purified using
multimodal chromatography using GE Healthcare's identified media.
12 Borgvall cites EP 07114856.3, which was published as EP 2 027 875 Al
(published Feb. 25, 2009) ("EP '875").
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Application 13/638,234
According to Borgvall, its inventors did not develop multimodal
chromatography for purifying proteins like F8, but wanted to use the
already-existing technique because it was a known tool useful for purifying
proteins, generally. Borgvall 3:46-53. What the Borgvall inventors
recognized was that the potential harshness of conditions for such
techniques, i.e., severely acidic or basic conditions, made the technique of
questionable use for purifying an unstable protein like F8. Id. at 3:54---62.
To overcome this issue, the Borgvall inventors identified that the mild
elution conditions (near neutral pH) disclosed by Wang 13 could be used with
the aforementioned multimodal chromatography and disclosed combining
these techniques, in combination with those described in EP '643 (increased
salt concentration for stabilization), along with using an amino acid buffer
solution for elution. Id. at 3:62--4:31; see also Spec. 12:16-25.
Appellants cite Putnam, 14 originally submitted by Appellants years
ago during prosecution, but not on appeal, as well as Appendices Exhibits
A-L, as support for their contention that F8 and F9 are so different that one
would not reasonably expect they could be purified using the same
technique. Appeal Br. 17-23. Neither Putnam nor any of the exhibits
Appellants submitted with their Appeal Brief explicitly or inferentially say
as much. Appellants present substantial evidence that the F8 and F9 proteins
have chemical and physical differences, e.g., size, shape, isoelectric point,
hydrophobic residue distribution, etc. Appeal Br. 15-23. But, is there no
13 Wang et al., Coagulation FVIII, structure and stability, 259 INT'L J.
PHARMA. 1-15 (2003) ("Wang").
14 FRANK W. PUTNAM, THE PLASMA PROTEINS STRUCTURE, FUNCTION, AND
GENETIC CONTROL, 2ed. Vol. III, 448-56 (1977) ("Putnam").
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Application 13/638,234
objective evidence that these differences matter in practice in carrying out
purification with a multimodal resin or would have mattered in the mind of
the skilled artisan having Borgvall before them; Appellants present only
attorney argument on this contention. "Attorneys' argument is no substitute
for evidence." Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir.
1989).
In fact, the evidence found in the prosecution history, discussed
below, supports a contrary position, that of the Examiner, which is that the
two proteins at issue would essentially be treated the same when considering
their isolation/purification. Borgvall itself, as noted above, indicates that
multimodal chromatography is a tool for purifying proteins, generally.
Borgvall 3:47--48.
EP '875, cited in Borgvall (at 3:47-52; and submitted during
prosecution on Sept. 28, 2012), discloses a process for purifying a target
protein and, significantly, discloses that the particular protein fractions for
isolation are plasma proteins including human blood clotting factors F9 and
F8, among others, using GE Healthcare's Capto MMC resin. EP '875 ,r 50,
claim 10.
WO '620, cited in Appellants' Specification (at 5:18-22; and
submitted during prosecution on May 16, 2013), discloses a process for
purifying a target protein using multimodal chromatographic material and
teaches that such target proteins can be selected from human blood clotting
factors F8 and F9, among others, and that the chromatographic media can be
GE Healthcare's Capto MMC resin. WO '620 abstract, 17:4--8, 18:5-8,
claim 10.
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Application 13/638,234
EP '634, cited in Appellants' Specification (at 12: 16-25; and
submitted during prosecution on Mar. 8, 2016), discloses a method for
isolating proteins and, like the others, lumps together "protein" as meaning
plasma proteins including human blood clotting factors F9 and F8, among
others.
None of these references distinguishes between F8 and F9 when
considering purification techniques, even in view of their known chemical
and structural differences. In fact, each teaches using the same general
purification techniques, which include the multimodal chromatographic
technique described in the appealed Specification, i.e., using GE
Healthcare's Capto MMC resin, to purify F8 and F9. Based on this
evidence, it is apparent that Appellants' arguments that the differences
between the F8 and F9 would have made substituting one for the other in a
protein purification process too unpredictable in the eyes of the skilled
artisan are unsubstantiated by a preponderance of the evidence. We are
therefore not persuaded by these arguments.
Appellants also argue Morfini is not prior art. Appeal Br. 25. This
argument is not persuasive. The Examiner does not cite Morfini as prior art,
but only as evidence of the general knowledge in the field relating to F8 and
F9 and their purification. See, e.g., Final Action 10. Moreover, even
without considering Morfini, it is apparent, based on the evidence from the
prosecution history discussed above ( and from Borgvall and Butenas,
generally), that the knowledge in the field relating to the purification of F8
and F9, particularly when coupled with the disclosure of Borgvall, renders
the claimed invention obvious.
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Appellants present an argument that the Examiner is, essentially,
estopped from brining the appealed rejections because they are too similar to
rejections made earlier in prosecution over different prior art, which were
withdrawn. Appeal Br. 11-13. Appellants identify no law or rule
supporting this position and we are not persuaded by this argument.
Regarding claim 24, Appellants argue that it requires arginine at a
concentration of0.1---0.5M and Borgvall uses a concentration of0.8M in its
working examples, so the claims are not obvious over such a disclosure.
Appeal Br. 27. This argument is not persuasive. "[A] reference is not
limited to the disclosure of specific working examples." In re Mills, 470
F.2d 649,651 (CCPA 1972)). Borgvall discloses the concentration of the
amino acid arginine is from about 0.4M to about I.OM. Borgvall 4:51-56.
"A prima facie case of obviousness typically exists when the ranges of a
claimed composition overlap the ranges disclosed in the prior art." In re
Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Appellants have provided
no evidence that the claimed range is critical so as to distinguish over the
prior art.
Regarding the rejection of claims 12-16, Appellants argue
that Adams, Foster, Bumouf and Roberts add nothing to the
disclosure of Borgvall to overcome its deficiencies and teach a
method of purifying FIX. Additionally, Appellant[ s] contend[]
that in view of the arguments presented above, none of Adams,
Foster, Bumouf or Roberts overcome the deficiencies of
Borgvall in view of Butenas and evidenced by Morfini.
Appeal Br. 27. Thus, Appellants present no different arguments for these
claims and the respective rejection; we conclude these claims fall with claim
1, which is representative, for the reasons set forth above.
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SUMMARY
The obviousness rejections under 35 U.S.C. § 103 are each affirmed.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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