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Application for Patent filed October 8, 1987, Serial No. 07/107,392. Anti-HIV Active 3'-Fluoro-Purine-2', 3'-Dideoxyribosides.
3. A pharmaceutical composition in unit dosage form, which comprises a pharmaceutically acceptable excipient, combined with an amount of an active ingredient which is selected from the group consisting of 3'-fluoro-2, 6- diaminopurine-2', 3', -dideoxyriboside and 3'-fluoro-2', 3'-dideoxyguanosine, effective to treat retroviral diseases in an animal or patient to whom one or more unit doses of said composition are administered.
6. A pharmaceutical composition as claimed in claim 3, comprising said active ingredient in a concentration ranging from 0.1-100% by weight.
15. A method for the treatment of a retroviral disease which comprises administering a pharmaceutically acceptable excipient, combined with an amount of a drug which is selected from the group consisting of 3'-fluoro-2, 6- diaminopurine-2', 3'-dideoxyriboside and 3'-fluoro-2', 3'-dideoxyguanosine to a patient suffering from a retroviral disease, effective to treat said retroviral disease.
27. A method for treating human cells which comprises administering a pharmaceutically acceptable excipient, combined with an amount of an active agent which is selected from the group consisting of 3'-fluoro-2, 6- diaminopurine-dideoxyriboside and 3'-fluoro-2', 3'-dideoxyguanosine effective to inhibit the replication and effects of HIV in human cells to which the administration is effected.
Retroviruses In Human Lymphoma/Leukemia, Miwa et al. (ed.), Japan Sci. Soc. Press, Tokyo, Japan, pages 227-288 (1985).
Sandstrom et al. (Sandstrom), "Antiviral Therapy In AIDS: Clinical Pharmacological Properties And Therapeutic Experience To Date", Review Article In DRUGS, 34, pages 373-390 (1987).
Okie, "Higher Cancer Rate Seen In Users of AIDS Drug", News Article in Washington Post, page A-3 (August 15, 1990).
*2 Sternberg et al. (Sternberg), "Doubts Remain About The Therapy To 'Cure' AIDS", News Article In Atlanta Journal-Constitution, Atlanta, GA, pages A1 and A-14 (June 6, 1990).
Altman, "AIDS Epidemic Puts An Unusual Microbe Under New Scrutiny", News Article In The New York Times Medical Science, page C-3 (June 26, 1990).
Baum et al. (Baum), "AIDS Vaccine, Drug Research Advancing In Several Fronts", News Article In Chemical & Engineering News, American Chemical Society, pages 7-15, see page 15 beginning at the last full paragraph of column 1 (July 16, 1990).
Gladwell et al. (Gladwell), "Researcher Sees Second Possible Cause Of AIDS", News Article In Washington Post (June 21, 1990.
Yarchoan et al. (Yarchoan), "Strategies For The Pharmacological Intervention Against HTLV-III/LAV", AIDS Modern Concepts And Therapeutic Challenges, Maracel Dekker, Inc., New York, pages 335-360 (1987).
II. Claims 3, 5, 6, 8, 10, 12, 23, 24, and 26 under 35 USC § 102(b) as anticipated by Zajtseva, either the USSR Inventor's Certificate or the Chemical Abstracts citation.
III. Claims 3, 10, 15, and 18 under 35 USC § 112, first paragraph, as being nonenabled.
IV. Claims 23 and 27 under 35 USC § 112, first and second paragraphs.
V. Claims 3 through 12 and 23 through 26 under 35 USC § 112, second paragraph, as being indefinite.
VI. Claims 3, 10, 15, 18, 23, 25, and 27 under 35 USC § 112, second paragraph, as being indefinite.
The claimed subject matter is directed to pharmaceutical compositions in unit dosage form which comprise as an active ingredient either 3'-fluoro-2, 6- diaminopurine-2', 3' dideoxyriboside (FddDAPR) or 3'-fluoro-2', 3'- dideoxyguanosine (FddGuo) and the use of such compositions in treating retroviral diseases such as AIDS or AIDS-related diseases or in treating human cells to inhibit the replication and effects of HIV in such cells.
The present specification sets forth that the claimed active ingredients, FddDAPR and FddGuo, were discovered during research for new potential anti-retroviral drugs. Appellants disclose in the paragraph bridging pages 2-3 of the specification that therapeutic compositions which contain these active ingredients are useful for treating AIDS, AIDS-related diseases and other retroviral diseases such as hepatitis B in humans. The working examples of the specification set forth certain in vitro testing activity which demonstrates anti-viral activity of the two active ingredients. Included in the in vitro testing are tests which determine the cytopathogenic effect of the active compounds on HIV in human T-lymphocyte cells as well as the inhibitory effects of the active ingredients on HIV antigen expression in infected human cells.
*3 It is apparent from the claims on appeal as well as the supporting specification that the primary utility of the pharmaceutical compositions which comprise FddDAPR and FddGuo resides in the treatment of humans who are either HIV positive or suffering from a retroviral disease, AIDS or AIDS-related disease. It is the inclusion of such human efficacy in the treatment of these diseases that forms the basis of the examiner's questioning of the utility and enablement of the claimed invention.
Here, appellants do set forth a statement of utility which corresponds in scope to the subject matter claimed. Therefore, it is the examiner's initial burden to establish that those skilled in this art would question the objective truth of the asserted utility, i.e., that pharmaceutical compositions containing FddDAPR or FddGuo would be useful in in vivo treatment of retroviral diseases, AIDS or AIDS-related diseases.
In support of her assertion that those skilled in the art would question the objective truth of these asserted utilities, the examiner relies upon Sandstrom, Mitsuya, Okie, Sternberg, Altman, Gladwell, and Baum. Of these references, we find Sandstrom and Mitsuya to be the most relevant. [FN3] Sandstrom is a review article concerning anti-viral therapy in AIDS which was published in 1987, the relevant time period in question. Sandstrom sets forth in the opening paragraph that the underlying cause of AIDS had so far eluded treatment. At page 374, it is stated that, while human viral infections are difficult to control, anti-viral therapy in the treatment of AIDS is the target of active research due to the role HIV plays in this disease. In reviewing the various anti-viral compounds which had been investigated up to that point in time, Sandstrom discloses the in vitro testing of these compounds followed by the then available results from clinical testing.
It is apparent from this reference that in 1987 those skilled in this art did not associate successful in vitro treatment of HIV infected human cells with any probability of achieving success in in vivo treatment of this disease. While the in vitro testing performed on these anti-viral compounds appears to be useful as a screening tool in order to determine which of these anti-viral compounds are candidates for further testing to determine if they possess in vivo utility, the in vitro tests were not predictive of in vivo efficacy. As set forth on page 386 of Sandstrom in the conclusion section, the development of in vitro assay systems is important in this area so that "rational selection of potential anti-viral compounds can be made" (emphasis added).
*4 The difficulty in concluding that a specific anti-viral compound will be useful in vivo in this field solely from in vitro testing is particularly seen from the results set forth in Sandstrom for the anti-viral compounds suramin and AZT. Suramin is a known anti-viral agent which was demonstrated by Mitsuya in 1985 to protect human T-cells against infectivity and cytopathic effects of HIV in vitro. The authors state in the second full paragraph of this article their belief that the in vitro results reported in this reference provide a rationale for a "carefully-monitored experimental trial" of this anti-viral compound in patients with AIDS to determine whether suramin does inhibit HIV replication in vivo. Thus, even the researchers who performed the work establishing the in vitro efficacy of suramin against HIV infected human cells were unwilling to predict that such in vitro work provided a basis to conclude that this compound would have in vivo efficacy.
We agree with the examiner's conclusion that one skilled in this art would question the asserted utility of FddDAPR or FddGuo in treating humans who are HIV positive or are suffering from AIDS. Further, to the extent that the claims on appeal are directed to broadly treating retroviral diseases or AIDS-related diseases, we point out that there is no evidence of record that is at all relevant to any condition or disease beyond AIDS. The examiner has correctly shifted the burden of proof to appellants to provide acceptable evidence or reasoning which establishes that those skilled in this art area would accept the in vitro testing set forth in the present specification as a proper basis to conclude that FddDAPR and FddGuo would be useful in in vivo treatment of humans afflicted with retroviral diseases broadly, are HIV positive, and/or suffering from AIDS or AIDS-related diseases.
Appellants' response to this rejection is two-fold. First, appellants question whether a prima facie case has been made out and if it is decided a prima facie case exists, appellants rely upon the declarations filed under 37 CFR § 1.132 of co-appellant Jan Balzarini and Dr. Martin Hirsch, a researcher having extensive experience in virology research including HIV.
*5 Throughout the Appeal Brief and Reply Brief, appellants have mischaracterized the examiner's position in regard to these rejections as being solely based upon an unsupported assertion of "incredible utility." As set forth above, these rejections, as set forth in the Examiner's Answer, are based upon credible evidence that those persons skilled in this art at the time of the present invention would not equate in vitro activity of anti-viral compounds of the type shown in the present specification with any in vivo efficacy in the treatment of retroviral diseases including AIDS or AIDS-related diseases. Certainly with the relative success achieved in AIDS therapy with AZT, it may not be "incredible" if other anti-viral compounds were shown to exhibit in vivo efficacy. The issue is whether the in vitro testing of FddDAPR and FddGuo set forth in the present specification as supplemented by the declarations of Balzarini and Hirsch would be accepted by those skilled in the art as a basis for concluding that these two compounds would be useful in in vivo treatment of these conditions.
The first declaration filed by Dr. Balzarini, (Paper No. 10, filed June 15, 1989) merely states Dr. Balzarini's belief that he "always tried to use conditions that would resemble the circumstances in vivo as much as possible." Dr. Balzarini concludes that the various in vitro assays set forth in this application are "appropriate for predicting the behavior of the test compounds in the living body and for determining the potential usefulness of the test compounds in vivo." However, Dr. Balzarini has failed to supply any evidence whatsoever in support of his belief and conclusion. Indeed, the evidence of record supports the opposite conclusion, i.e., that in vitro testing of anti-viral compounds is not in and of itself predictive of in vivo efficacy in the treatment of retroviral diseases broadly or specifically AIDS. The second declaration of Dr. Balzarini (Paper No. 16, filed February 28, 1990), does not address the issues raised under 35 USC § 101 and § 112, first paragraph.
5) I believe that the tests conducted and recorded in the specification demonstrate a reasonable basis for a conclusion that the 3'-fluoro-purine-2', 3'-dideoxyribosides may have utility in combatting diseases or syndromes causally related to HIV.
As apparent, Dr. Hirsch has only concluded that the test methods used in the present specification "may" establish that FddDAPR and FddGuo have utility in "combatting diseases and/or syndromes causally connected to HIV." The use of the word "may" by Dr. Hirsch in stating his conclusions is entirely consistent with the state of the art presented by Sandstrom and Yarchoan, i.e., in vitro testing of the type performed in the present specification is useful as a screening tool of potential anti-viral agents in the fight against AIDS, but any conclusion as to whether a specific anti-viral compound will, in fact, be effective in vivo is not predictive from the in vitro tests.
It is not proper for the Patent Office to require clinical testing in humans to rebut a prima facie case of lack of utility when the pertinent references which establish the prima facie case show in vitro tests and when they do not show in vivo tests employing standard experimental animals. (footnote omitted). 503 F.2d at 1392-93, 183 USPQ at 297.
We have carefully considered appellants' arguments in this regard but do not find that Langer requires reversal of these rejections. In Langer, the references relied upon by the PTO in establishing the prima facie case of lack of utility only disclosed in vitro tests. The PTO's position as reported in that case was that only "the highest type of evidence (i.e.,--clinical testing in humans) is required to rebut the prima facie case." Thus, the statement from Langer relied upon by appellants was only expressing disapproval of the requirement of the PTO that human clinical testing was the only acceptable rebuttal evidence under the facts of that case.
We do not presume to tell appellants what evidence would be acceptable in rebuttal of these rejections. While we are not requiring human clinical trials, it may very well be that in 1987 or even now those skilled in this art would not accept anything short of such human clinical trials. There is no evidence of record that experimental animal models have been developed in this area which would be predictive of human efficacy. Compare In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980).
To the extent that appellants are arguing that AZT and a second anti-viral compound identified in the Appeal Brief as dideoxyinosine (ddI) have achieved a modicum of success in treating AIDS, we note that appellants have failed to make of record any evidence which establishes that the two compounds under consideration herein, FddDAPR and FddGuo, would have been considered so structurally similar to AZT or ddI that one would expect similar properties.
*7 Rejection I is affirmed.
There is no dispute that Zajtseva discloses FddGuo. Rather, the issue is whether this reference discloses unit doses of this compound having the effective amounts set forth in the various composition claims. In considering this rejection, we note that as the claims are presented on this appeal, the active ingredient may be its own excipient. See, e.g., claim 3 where the pharmaceutical composition may comprise 100% by weight of the active ingredient. [FN8] We also note that appellants set forth at page 3, lines 10-12 of the specification that the dose of the active ingredient may vary between 0.1 mg and 100 mg per kg of body weight. Zajtseva discloses in the paragraph bridging pages 5-6 of the translation that 120 mg of FddGuo were recovered and in the first paragraph of page 7 of the translation that solutions of FddGuo were prepared for testing. As set forth in the Table of the reference, various unit doses of FddGuo were prepared and tested in the assay of that reference.
Inasmuch as Zajtseva discloses FddGuo, reports the isolation of 120 mg. of the substance, and prepares unit doses of this compound, we agree with the examiner's conclusion that claims 3, 5, 6, 8, 10, 12, 23, 24, and 26 are anticipated.
Appellants argue that this reference does not disclose the various "effective amounts" set forth in these claims. However, as noted above, these so-called effective amounts translate into a wide range of finite doses. On this record, it is proper to shift the burden of proof to appellants to show that any of the compositions containing FddGuo disclosed in this reference do not, in fact, fall within the wide range of "effective amounts" encompassed by these claims.
From the statement of this rejection at page 6 of the Answer, it appears that the examiner is concerned with the breadth of these terms. However, it is unclear precisely what the examiner would require appellants to do. Merely concluding that the claims must be limited in accordance with "the specific embodiments" without pointing out what "specific embodiments" the claims should be limited to leaves appellants and us to only surmise what is on the examiner's mind.
To the extent these claims are separately rejected for these reasons under 35 USC § 112, first paragraph, the rejection is reversed.
We first note that while this rejection is nominally made under the first and second paragraphs of 35 USC § 112, the examiner has only set forth reasons why claims 23 and 27 are indefinite under the second paragraph. Thus, we reverse this rejection to the extent it is based upon the first paragraph of this section of the statute.
*8 Turning to the specific reasons set forth on pages 6-7 of the Examiner's Answer, we find the examiner's position to be that claims 23 and 27 are "excessive in scope and unclear" in that the phrase "human cells" may encompass a human host.
We disagree with the examiner that claims 23 and 27 are indefinite. The term "human cells" is broad as observed by the examiner, reading upon human cells found in either an in vitro cell culture or in a living body. However, we do not find that the breadth of this term renders the claims indefinite. The examiner has not articulated any reason why one of ordinary skill in the art would have any difficulty ascertaining the metes and bounds of these claims.
The examiner considers claims 3 through 12 and 23 through 26 to be indefinite since the independent claims, claims 3, 10, and 23, differ only by setting forth a different disease as the reference point for the stated effective amount.
Claims 3, 10, and 23 are directed to pharmaceutical compositions in unit dosage form where the amount of the active ingredient is in an amount effective to treat the stated disease when one or more of the unit doses of the composition are administered. Appellants argue that the effective amounts in these claims "may actually turn out to be effective amounts" (Reply Brief, page 10).
As set forth in In re Moore, 439 F.2d 1232, 169 USPQ 236 (CCPA 1971), the definiteness of claim language must be determined by analyzing the language used in light of the supporting specification and prior art. Here, reference to the supporting specification does not aid in determining how these claims differ from one another. The specification does not use the terms "unit dosage" or "unit dose." The only discussion of dosages appears in the above referenced portion of the specification at page 3, lines 10-12 where the single range of valves is disclosed. This portion of the specification does not set forth any information as to how the dosages for any two disease states to be treated may differ. Absent definitions for the terms "unit dosage" and "unit dose" as they appear in these claims and/or any guidelines in the specification as to how these dosages would in fact differ depending on the specific disease to be treated, one is left to surmise and conjecture in trying to determine which, if any, of the present composition claims may be infringed by compositions comprising either of the two active ingredients with a pharmaceutically acceptable excipient. In re Hammack, 427 F.2d 1378, 166 USPQ 204 (CCPA 1970).
This was a new ground of rejection in the Examiner's Answer. In response, appellants did not contest the merits of this rejection. Rather, an amendment was filed which amended claims 3, 10, 15, 18, 23, and 25, but not claim 27, to specifically recite that the dideoxy functions are 2', 3' in accordance with the examiner's suggestion. While the Supplemental Examiner's Answer (Paper No. 29, filed January 22, 1991) did not refer to this amendment, the amendment has been entered in this file. Apparently the examiner is of the opinion that this amendment overcomes this rejection in regard to claims 3, 10, 15, 18, 23, and 25. Accordingly, we reverse Rejection VI as it includes claims 3, 10, 15, 18, 23, and 25 as being moot, [FN12] and affirm the rejection as it includes claim 27.
*9 The decision of the examiner is affirmed.
FN1. Our consideration of both of these references is based upon an English translation of the USSR inventor's certificate prepared by the Patent and Trademark Office (PTO), a copy of which is attached.
FN2. While the examiner has presented these rejections separately in the Examiner's Answer, we have combined them for consideration in this appeal since they present similar issues. In re Gardner, 475 F.2d 1389, 1392, 177 USPQ 396, 398 (CCPA 1973).
FN3. The examiner has relied upon Okie, Sternberg, Altman, Gladwell and Baum as evidence that use of the anti-viral drug AZT in treating AIDS may be accompanied by severe side effects or that there may be other causative factors beyond HIV infection for this disease. We do not find the examiner's concern in regard to possible side effects occurring from treatment of AIDS patients with other anti-viral drugs to be particularly relevant to the present inquiry since the occurrence of side effects does not raise the issue of whether the anti-viral drug in and of itself exhibits in vivo anti-viral activity. Whether such side effects outweigh the anti-viral utility in treating specific patients suffering from specific diseases is a matter left to the appropriate medical regulating authorities and/or the treating physician. To the extent these references may point to a second separate causative factor for AIDS beyond HIV infection, such references do not raise the question as to whether HIV itself is a causative factor.
FN4. The present specification does not assert or provide any evidence that either of the present active ingredients would be useful in combination therapy for any of the disclosed diseases.
FN5. Yarchoan is another reference of record which establishes that in the relevant time frame, 1987, workers in this field did not predict in vivo efficacy of anti-viral agents in the treatment of AIDS solely from successful in vitro testing. At page 347, in discussing suramin, Yarchoan discloses that "a similar failure of in vitro activity to translate into clinical efficacy has been observed with other antiviral drugs, 5-iodo-2'-deoxyuridine." In discussing the compounds rifabutine and alpha-IFN on page 354, Yarchoan states that efforts were then underway to determine if rifabutine has activity against HIV in patients with AIDS and that it was presently unknown if alpha-IFN is virustatic when administered to patients, another indication that successful in vitro testing of these anti-viral compounds was not automatically predictive of in vivo efficacy.
FN6. It should be noted that under the facts in Langer, the court reversed the rejection under 35 USC § 101 of claims directed to a species of the active ingredient under consideration therein based upon in vivo testing using appropriate experimental animals, i.e., rats. As to the broader generic claims, it was held that the evidence submitted in that case was insufficient to prove even indirectly the utility of the remaining members of the claimed genus.
FN7. To the extent that the examiner has attempted to explain the basis of allowance or has questioned the validity of certain of the cited patents (Examiner's Answer, paragraph bridging pages 14-15 and page 16, first full paragraph), she is referred to M.P.E.P. 1701 (PTO employees are not to discuss questions of validity or invalidity of issued U.S. patents with persons outside the PTO).
FN8. We elect to interpret the claims in this manner for to do otherwise would necessitate the conclusion that claims such as claim 3 are improper dependent claims since they would exclude the excipient required by the independent claims.
FN9. We note that the examiner did not include claim 9 in this rejection. This claim further limits the composition of claim 9 to one in which the form is selected, inter alia, from powders and solutions. If this subject matter is prosecuted in a continuing application, the appellants and the examiner should consider the relevant disclosure of Zajtseva of recovering FddGuo in crystalline form and forming solutions therefrom as it may apply to claim 9.
FN10. The examiner did not include the claims which depend from these independent claims in this rejection. It is unclear whether this failure was an inadvertent error on the part of the examiner or whether the dependent claims are directed to the otherwise unidentified "specific embodiments." Our reversal of this rejection renders this point moot.
FN11. Our treatment of this rejection presumes that the language used in these claims is described in the original disclosure of the application under 35 USC § 112, first paragraph because the examiner has not rejected these claims under this section of the statute. Since the terms "unit dosage" and "unit dose" as used in these claims are not used in the original disclosure of this application, the issue arises as to whether the concepts now claimed were described in the original disclosure. If prosecution of this subject matter is resumed in a continuing application, the appellants and the examiner should ensure that all claim language is adequately supported in the original disclosure of this application.
FN12. We point out that claim 4 suffers from the same defect which necessitated this new ground of rejection. In view of appellants' acquiescence in this rejection by submitting the above referenced amendment, we will assume that an appropriate amendment will be forthcoming for claim 4 on appeal if prosecution is resumed in a continuing case.

References: § 102
 § 112
 § 112

V. 
 § 112
 § 112
 § 1
 § 101
 § 112
 § 112
 § 112
 § 101
 § 112