Ex parte Goodship et al.

Board of Patent Appeals and Interferences

Sep 27, 2000

08159096 (B.P.A.I. Sep. 27, 2000)

The opinion in support of the decision being entered today was not written for
publication and is not binding precedent of the Board.

Paper No. 20

UNITED STATES PATENT AND TRADEMARK OFFICE

__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ALLEN E. GOODSHIP, PETER WALKER, DONAL S. McNALLY,
TIMOTHY J. CHAMBERS, and JONATHAN GREEN
__________

Appeal No. 1997-2751
Application No. 08/159,096
__________

ON BRIEF
__________

Before WILLIAM F. SMITH, MILLS, and GRIMES, Administrative Patent Judges,

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the examiner’s
final rejection of claims 1 -14, all of the claims pending in the application. All of
the claims are drawn to a method of treating bone fractures in mammals by
administering one of a class of diphosphonate compounds.
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The examiner relies on the following references:1

European Patent
Gall et al. (Gall) 0 252 505 Jan. 13, 1988

Henricson et al. (Henricson), “The Effect of Diphosphonates on Fracture Healing
in Rats Stuidied with Monoclonal Antibodies,” Calcified Tissue Int., Vol. 39
(Suppl.), page A74 (1986).

Kanis, “Treatment of Osteoporotic Fracture,” The Lancet, pp. 27-33 (1984).

Fitton et al. (Fittion), “Pamidronate: A Review of its Pharmacological Properties
and Therapeutic Efficacy in Resorptive Bone Disease,” Drugs, Vol. 41, pp. 289-
318 (1991).

Claims 1-14 stand rejected under 35 U.S.C. § 103 over the combination of
Fitton, Gall, Kanis, and Henricson.
We reverse and enter a new ground of rejection under 37 CFR § 1.196(b).
Background
As explained in Appellants’ specification, bisphosphonate (aka
diphosphonate) compounds are used clinically to inhibit excessive bone
resorption associated with diseases such as osteoporosis and Paget’s disease.
Because bisphosphonates inhibit bone resorption, researchers in the prior art
generally expressed an expectation that they would interfere with the normal
fracture-healing process. Appellants allege that, contrary to these expectations,
certain methanebisphosphonic acid derivatives actually aid in the healing of bone
fractures. Appellants state that these compounds “promote a more rapid and
stronger fracture healing.” Specification, page 2.

1 The Examiner in her Answer did not provide proper citations for the references by Fitton, Kanis,
or Henricson. See MPEP § 707.05(e) (a correct citation to an article in a periodical “includes the
author(s) and title of the article and the title, volume number, issue number, date and pages of the
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Discussion
The pending claims are drawn to a method of treating fractures in
mammals by administering a methanebisphosphonic acid compound. The
examiner rejected all of the claims as obvious over Fitton, Gall,2 Kanis, and
Henricson. According to the examiner, Fitton discloses the use of
bisphosphonate in “bone fracture medications” and Gall teaches use of
bisphosphonates when the process of bone formation and breakdown is
disturbed. The examiner cited Kanis and Henricson as showing “the breadth and
wealth of knowledge of diphosphonates in bone therapy.” Examiner’s Answer,
page 3. The examiner concluded that any differences between the prior art and
the claimed method amounted merely to optimizing parameters, and therefore
the cited prior art would have made the obvious the claimed method.
Appellants argue that the references cited by the examiner do not support
a prima facie case of obviousness, for several reasons. Appellants argue that
resorptive bone disorders (e.g., osteoporosis) are caused by a mechanism that is
completely different from bone fracture. Appellants also argue that treatments for
the two types of disorders are also completely different, in that the systemic

periodical.”). Fortunately, Appellants in their Brief provided full citations to the references relied
on by the Examiner, allowing us to discern the basis for the rejection.

2 We note that the examiner relied on EP 252505 (Gall), which is in German, in her statement of
the rejection but cited to a U.S. Patent when discussing what is disclosed by Gall. We assume
the U.S. Patent cited is 4,942,157 (Gall), which Appellants indicate in their Brief corresponds to
EP 252505. We also note that U.S. Patent 4,942,157 issued on July 17, 1990, making it prior art
with respect to the instant claims under 35 U.S.C. § 102(b). We are baffled by the examiner’s
reliance on a reference in German when a corresponding English language reference was in the
record. It should be obvious that when two equivalent references are available, one in English
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inhibition of bone resorption that is the basis for treating resorptive bone
disorders would not have been expected to aid fracture healing. Finally,
Appellants assert that the Examiner misread the prior art to suggest that fracture
healing and treatment of bone loss require the same type of treatment, and
ignored teachings in the prior art that would have led a skilled artisan to expect
that bisphosphonate compounds would likely have a deleterious effect on
fracture healing.
“It is well-established that before a conclusion of obviousness may be
made based on a combination of references, there must have been a reason,
suggestion, or motivation to lead an inventor to combine those references.”
Pro-Mold & Tool Co. v. Great Lakes Plastics Inc., 75 F.3d 1568, 1573,
37 USPQ2d 1626, 1629 (Fed. Cir. 1996).
Although couched in terms of combining teachings found in the
prior art, the same inquiry must be carried out in the context of a
purported obvious “modification” of the prior art. The mere fact that
the prior art may be modified in the manner suggested by the
Examiner does not make the modification obvious unless the prior
art suggested the desirability of the modification.

In re Fritch, 972 F.2d 1260, 1266, 23 USPQ2d 1780, 1783-84 (Fed. Cir. 1992).
Here, the examiner has concluded that it would have been obvious to modify the
prior art methods by administering bisphosphonate compounds, not to prevent
future bone fractures, but to treat fractures after they occur.
Having carefully considered the evidence and reasoning presented by
Appellants and the examiner, we find ourselves in agreement with Appellants

and one not, the reference in English should be preferred.
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that the cited prior art provides no “reason, suggestion, or motivation” to modify
the prior art in such a way. Rather, the cited references suggest that
bisphosphonates would have been expected to interfere with, not aid, the
process of bone fracture healing. For example, Gall teaches use of
bisphosphonates to treat a variety of diseases (e.g., osteoporosis and Paget’s
disease) but does not suggest that such compounds would be useful to treat a
bone fracture. Similarly, Fitton teaches use of bisphosphonates to treat Paget’s
disease and thereby reduce the risk of bone fractures, but says nothing to
suggest that the compounds would be useful to treat fractures after they occur.
In fact, one of the references relied on by the examiner actually teaches away
from the claimed method. Kanis states that inhibitors of bone resorption such as
bisphosphonates may “increase the risk of microfracture or delay their repair and
lead to skeletal failure . . ., by reducing the rate of remodeling of damaged bone,
inhibiting callus formation, or both.” Page 27.
Appellants in their Brief pointed out that the bisphosphonates pamidronate
and etidronate have been reported in the scientific literature to inhibit fracture
healing. Appellants cited, among others, the references in the record by Reid et
al. and Finerman et al. as disclosing adverse effects of bisphosphonates on
fracture healing. In response, the examiner stated that Appellants’ reliance on
Reid and Finerman was “not part of the original rejection and any response to it
would be considered new grounds of argument.” Examiner’s Answer, page 4.
The examiner erred in not addressing the teachings of Reid and Finerman
cited by Appellants. “If a prima facie case [of obviousness] is made in the first
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instance, and if the applicant comes forward with reasonable rebuttal, whether
buttressed by experiment, prior art references, or argument, the entire merits of
the matter are to be reweighed.” In re Hedges, 783 F.2d 1038, 1039, 228 USPQ
685, 686 (Fed. Cir. 1986). The fact that the examiner did not rely on these
references in her rejection does not make a response to their citation by
Appellants a new ground of argument. On the contrary, the examiner is required
to reweigh the merits of the entire rejection in view of whatever argument, prior
art, or experimental evidence is presented by an applicant in rebuttal. See id.;
see also In re Rinehart, 531 F.2d 1048, 1052, 189 USPQ 143, 147 (CCPA 1976)
(“When prima facie obviousness is established and evidence is submitted in
rebuttal, the decision-maker must start over.”).
New Ground of Rejection
Under the provisions of 37 CFR § 1.196(b), we make the following new
ground of rejection: The specification is objected to, and claims 1-14 are
rejected, under 35 U.S.C. § 112, first paragraph, because the specification does
not enable a person of skill in the art to make and use the claimed invention. As
evidence supporting our conclusion of non-enablement, we rely on the
references of record by Alpar, Kanis, Reid, Finerman, Henricson, and Lenehan.
Appellants’ specification accurately summarizes the expectation of those
skilled in the art that bisphosphonate compounds would interfere with, not aid,
the fracture healing process. See the Specification at page 1:
As the compounds bind to bone mineral and inhibit bone resorption,
there has been general concern that bisphosphonates could have a
deleterious effect on callus formation and remodelling, which is an
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essential part of the fracture repair process. Kanis, for example,
teaches in Lancet 1984, 27-33 that bisphosphonates, as inhibitors
of bone resorption, may indeed halt skeletal losses but on the other
hand delay the repair of microfractures by reducing the rate of
remodelling of damaged bone and inhibiting callus formation. As
another example, Reid et al. in Lancet 1988, 143-146 found that
bisphosphonate treatment, in this particular case done with
disodium pamidronate (= APD), caused a reduction in bone
formation and a very low rate of bone turnover which raised the
possibility of impaired microfracture repair. Furthermore, Alpar, in
J. Clin. Hosp. Pharmacy 9 (1984) 341-344, expressed the view that
the natural process of bone healing cannot be influenced by any
drug.

Furthermore, one commercially available bisphosphonate, disodium
etidronate, is even known to inhibit bone mineralization and to delay
callus formation and fracture healing in man and animals at doses
within the therapeutic range [see G.A.M. Finerman et al., Clin.
Orthopaed. Rel. Res. 120 (1976) 115-124; L. Flora et al., Metabol.
Bone Dis. Rel. Res. 4/5 (1981) 289-300].

The specification accurately summarizes the prior art. Alpar reviews the
bone healing process and concludes that “[i]t appears that this natural process
cannot be influenced by drugs.” Page 343. Kanis states that inhibitors of bone
resorption such as bisphosphonates may “increase the risk of microfracture or
delay their repair and lead to skeletal failure . . ., by reducing the rate of
remodeling of damaged bone, inhibiting callus formation, or both.” Page 27. In
addition, Reid states that administration of (3-amino-1-hydroxypropylidene)-1,1-
bisphosphonate causes a “very low rate of bone turnover,” and “raises the
possibility of impaired micro[]-fracture repair.” Page 145.
Experimental evidence generated by Finerman, Henricson, and Lenehan
confirmed these expectations. Finerman reported that withholding
diphosphonate treatment in two patients allowed fracture healing to proceed.
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Page 123, left-hand column. By contrast, a patient who was continued on
diphosphonate therapy after fracture showed “no healing of the fracture . . . 6
months later.” Id. When diphosphonate administration was discontinued, bone
union promptly occurred. Id.
Similarly, Henricson found that in rats treated with aminopropane
diphosphonate, bone fracture healing (in particular inductive callus and
enchondral bone formation) occurred more slowly than in control animals. In
addition, Lenehan found that administration of ethane-1-hydroxy-1,1-
diphosphonate caused a dose-dependent inhibition of fracture healing in dogs
(see the abstract). Lenehan also stated that the effects on humans would be
expected to be similar because of the similarity in bone remodeling between
humans and dogs (page 507).
Thus, the prior art in the record shows that those skilled in the art would
have expected administration of diphosphonate compounds to inhibit, rather than
aid, the healing of bone fractures. The evidence thus shows that those skilled in
the art would have doubted the efficacy of the claimed method, based on the
evidence available at the time of the invention.
The instant specification presents no evidence to show that this
expectation was incorrect. In fact, the record contains no evidence showing that
the compounds recited in the claims have any beneficial effect on fracture
healing. The specification contains a single example, which appears to be
prophetic. The example (pages 4-5 of the specification) is presented in the
present tense, suggesting that the work described had not actually been carried
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out. The example also does not specify what compound was administered,
further suggesting that a completed experiment is not being reported.
Confusingly, however, the example then presents “results,” suggesting
that some work had been done. On close inspection, however, it is apparent that
no actual results are presented. Again, specific results are not reported for a
specific compound and the rate of bone mineralization is reported as “e.g. 76%
greater in the treated group than the controls” (emphasis added). We therefore
conclude that the “results” reported in the specification are no more than what the
inventors hoped to achieve in an actual experiment. The manner in which the
specification presents this example is confusing at best, and possibly misleading
to the casual reader, but the example appears to be merely prophetic, rather than
an actual working example.
We are aware of only one piece of evidence in the record that might be
interpreted to support enablement of the instant claims. Lenehan shows that at
one specific dosage, administration of ethane-1-hydroxy-1,1-diphosphonate
caused some beneficial effect on fracture healing. See page 505, right-hand
column (“Biomechanical evaluation of fracture sites in group 2 [0.1 mg/kg/day]
revealed fracture-healing characteristics that exceeded those of controls.”).
However, this isolated result is not sufficient to outweigh the other record
evidence indicating nonenablement, for two reasons. First, the compound
administered by Lenehan, although a diphosphonate, is not within the scope of
the instant claims. Second, Lenehan expressed surprise that any dosage of
ethane-1-hydroxy-1,1-diphosphonate would benefit fracture healing. See page
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505, right-hand column (“The reason for this finding is unknown, since
mineralization rates are not increased nor has this dose level been previously
shown to increase activation frequency or appositional rate.”). Therefore, this
finding would not have led those skilled in the art to expect similar results from
treatment of fractures with other diphosphonates, such as those recited in the
instant claims.
As stated in In re Wright, 999 F.2d. 1557, 1561, 27 USPQ2d 1510, 1513
(Fed. Cir. 1993):
[w]hen rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of
protection provided by that claim is not adequately enabled by the
description of the invention provided in the specification of the
application; this includes, of course, providing sufficient reasons for
doubting any assertions in the specification as to the scope of
enablement. If the PTO meets this burden, the burden then shifts to
the applicant to provide suitable proofs indicating that the
specification is indeed enabling.

Factors that bear on whether claims are adequately enabled include:
(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state of
the prior art, (6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth of the
claims.

In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
After reviewing all of the evidence in the record in light of the Wands
factors, we conclude that the specification does not enable practice of the full
scope of the claimed invention without undue experimentation. In particular, we
note that the invention is of a nature which contradicts accepted scientific
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knowledge about the nature of fracture healing and the in vivo mechanism of
action of diphosphonates; that is, those of skill in the art expected that
diphosphonates would act to interfere with, rather than aid, fracture healing. In
addition, the state of the prior art was such that those skilled in the art would not
have considered practice of the claimed method to be feasible. Finally, the
specification lacks any working examples or actual data to counter the art-based
expectation that the claimed method simply would not work.
We conclude that the evidence of record provides sufficient basis for
doubting the assertions in the specification as to the scope of enablement, and to
shift the burden to Appellants “to provide suitable proofs indicating that the
specification is indeed enabling.” In re Wright, 999 F.2d at 1561, 27 USPQ2d at
1513.
Summary
We reverse the rejection of the claims as obvious over the references
cited by the examiner but enter a new ground of rejection based on non-
enablement.
This decision contains a new ground of rejection pursuant to 37 CFR
§ 1.196(b)(amended effective Dec. 1, 1997, by final rule notice, 62 Fed. Reg.
53,131, 53,197 (Oct. 10, 1997), 1203 Off. Gaz. Pat. & Trademark Office 63, 122
(Oct. 21, 1997)). 37 CFR § 1.196(b) provides that, “A new ground of rejection
shall not be considered final for purposes of judicial review.”

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TIME PERIOD FOR RESPONSE
37 CFR § 1.196(b) also provides that the appellants, WITHIN TWO
MONTHS FROM THE DATE OF THE DECISION, must exercise one of the
following two options with respect to the new ground of rejection to avoid
termination of proceedings (§ 1.197(c)) as to the rejected claims:

(1) Submit an appropriate amendment of the claims so
rejected or a showing of facts relating to the claims so rejected, or
both, and have the matter reconsidered by the examiner, in which
event the application will be remanded to the examiner. . . .

(2) Request that the application be reheard under § 1.197(b)
by the Board of Patent Appeals and Interferences upon the same
record. . . .

No time period for taking any subsequent action in connection with this

appeal may be extended under 37 CFR § 1.136(a).
REVERSED
37 CFR ' 1.196(b)

)
WILLIAM F. SMITH )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
DEMETRA J. MILLS )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
ERIC GRIMES )
Administrative Patent Judge )

Appeal No. 1997-2751
Application No. 08/159,096

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Michael W. Glynn
NOVARTIS Corporation
564 Morris Ave.
Summit, NJ 07901

EG/jlb