Pharmaceutical Chemistry Patent Blog

Ecolochem, Inc. v. Southern California Edison Co., 227 F.3d 1361 (Fed. Cir. 2000).

Facts:

Ecolochem owned two patents directed to methods of demineralization and deoxygenation of water. Ecolochem developed the underlying technology while contracting its water purification and supply services to Southern California Edison Company. Edison at the time was constructing its own water purification facility. Ecolochem filed suit against Edison upon completion of the project, alleging that Edison’s facility infringed Ecolochem’s patents. The district court granted partial summary judgment in favor of Edison and held that the claims of the two patents were invalid as either anticipated or obvious.

On appeal, the Court of Appeals for the Federal Circuit reversed and remanded for retrial, holding that disputed issues of material fact remained pertaining to evidence of secondary indicia of nonobviousness presented by Ecolochem.

Following a bench trial on remand, the district court found that Edison had willfully infringed Ecolochem’s patents. The court also found, however, that the infringed claims were invalid as obvious in light of a combination of prior art including references that taught the use of mixed-bed ion exchange resins. Ecolochem appealed the finding of invalidity regarding the claims of the ‘411 patent but did not assert the other patent on appeal.

Issues:

1. Whether process patent claims are anticipated by prior art articles or by a scientist’s public presentation if the entire process is not fully described in any one reference.

2. Whether an invention that combines two known elements is obvious when nothing in the prior art as a whole suggests, teaches, or motivates one of ordinary skill in the art to make the combination.

3. Whether evidence of secondary considerations can rebut a prima facie case of obviousness and raise a genuine issue of fact that requires a remand for trial of the issue.

Holding:

1. No. Prior art references that do not expressly teach each and every element of the process described in a patent do not anticipate the patent.

2. No. Obviousness cannot be established by combining the teachings of the prior art unless the prior art contains a teaching, suggestion or motivation to combine.

3. Yes. Evidence of secondary indicia of nonobviousness may raise a material issue of fact necessitating a remand for trial on the issue.

Discussion:

The Court of Appeals for the Federal Circuit reviewed de novo the district court’s finding that the claims were obvious and invalid. The court noted that the prior art taught the use of hydrogen to deoxygenate water but did not teach the deoxygenation of water using hydrazine with mixed-bed ion exchange resins. With the exception of claim 20, the court reversed the district court’s finding that Ecolochem’s claims were anticipated by a scientist’s public presentation because a key part of the claimed process had been omitted from the presentation. The court found that the presentation included every limitation of claim 20 and affirmed the district court’s finding of invalidity regarding that claim.

The court held that the combination of two prior art references does not render patent claims obvious absent a teaching, suggestion, or motivation to combine the information and where there was evidence of teaching away in the prior art. Here, the court held that the prior art taught away from the mixed-bed ion exchange process and that the claims were therefore not obvious in light of secondary indicia of nonobviousness.

The Federal Circuit considered evidence of secondary indicia of nonobviousness offered by Ecolochem to overcome a prima facie showing of obviousness for claim 20 and affirmed the district court’s determination that the claim was obvious. The court reasoned that the lack of evidence of copying by others in addition to evidence that showed that Ecolochem’s process was not developed in response to a “long felt need” pointed more strongly toward a finding of obviousness than commercial success and teaching away supported the opposite conclusion.

Disposition:

Affirmed with regard to the district court’s finding that claim 20 was invalid, reversed with respect to all of the other claims, and remanded for a determination of damages to Ecolochem for infringement of the remaining valid claims.

3D Systems, Inc. v. Aarotech Labs., Inc., No. 97-1514, 1998 U.S. App. Lexis 28583, 160 F.3d 1373, 48 U.S.P.Q.2d (BNA) 1773 (Fed. Cir. Nov. 12, 1998).

Facts:

3D Systems filed a patent infringement suit against Aarotech, Aaroflex, and Young in the Central District of California. The defendants moved to dismiss for lack of personal jurisdiction. The district court granted the motion and dismissed the claims against all of the defendants, finding that the plaintiff had not established the elements for personal jurisdiction under the Ninth Circuit’s due process test.

Aarotech, the parent corporation of Aaroflex, was incorporated in Oklahoma and had its principle place of business in Virginia but had taken no actions in the state of California.

Aaroflex, a subsidiary of Aarotech, was incorporated in West Virginia and had its principle place of business in Virginia. As of the date of the district court’s decision, Aaroflex had sold a total of five machines, none of which had been shipped, and none of which had been sold in California. Promotional materials had been distributed in California, however.

Young was the President and Chairman of the Board of Aaroflex and the CEO of both Aaarotech and Aaaroflex and resided in Washington, DC.

Issue:

1) What personal jurisdiction law does the Federal Circuit apply – its own or that of the lower court?
2) Were Aaroflex’s promotional materials and price quotations offers for sale under 35 U.S.C. § 271(a), despite stating that they were not an offer for sale until executed by recipient?

Holding:

1) The Federal Circuit applies its own personal jurisdiction law, deferring to the state’s highest court’s interpretation of the state’s long arm statute.
2) Yes. Using the conceptualization of “offer to sell” under federal law and not the law of the state, the promotional materials were an offer for sale.

Discussion:

The Federal Circuit applied the Akro test for minimum contacts (see Akro Corp. v. Luker, 45 F.3d 1541, 1545-46, 33 U.S.P.Q.2d 1505, 1508-09 (Fed. Cir. 1995)). The three prongs of the Akro test are:

1) whether the defendant purposefully directed its activities at the forum,
2) whether the claim arises out of or relates to those activities, and
3) whether an assertion of personal jurisdiction is reasonable and fair.

Whether the second prong had been satisfied depended on whether the promotional materials constituted an offer for sale. The Federal Circuit held that “offer to sell” under 35 USC § 271 was intended to prevent potential infringers from generating interest in an infringing product to the detriment of the patentee. The Federal Circuit held that the promotional materials constituted offers for sale and that minimum contacts had been established, and that therefore the district court had had personal jurisdiction over Aaroflex.

Disposition:

Affirmed-in-part as to the district court’s finding that it lacked personal jurisdiction over Aarotech and Young, reversed-in-part as to the district court’s finding that it lacked personal jurisdiction over Aaroflex, and remanded.

Facts:

Gould and Schawlow filed patent applications directed to lasers. The parties became involved in an interference. Gould was the junior party and sought to establish earlier conception and reasonable diligence through reduction to practice. Gould produced evidence including a notebook, notarized papers, and his wife’s testimony. The Board of Patent Appeals and Interferences awarded priority of the invention to Schawlow, finding that Gould had established neither earlier conception nor diligence through reduction to practice.

Issue:

What must the applicant prove to establish earlier conception and reasonable diligence through reduction to practice?

Holding:

1) Rule for Interference

In order for the junior party to prevail in an interference, the party must prove by a preponderance of the evidence (1) conception of the invention and (2) reasonable diligence in reducing it to practice through reduction to practice (usually a constructive reduction to practice established by filing the patent application).

2) Conception:

The court held that Gould had not established an earlier reduction to practice. Gould relied on pages in a notebook that he had had notarized. The court found that the notebook pages were insufficient to establish Gould’s earlier conception.

Rule for Conception: The court held that the evidence must show “a complete conception, free from ambiguity” or doubt sufficient to enable the inventor or a person having skill in the art to reduce the invention to practice without “further exercise of inventive skill”. See Mergenthaler v. Scudder, 11 App.D.C. 264 (D.C. Cir. 1897).

3) Diligence through Reduction to Practice:

The court held that Gould had not established diligence through reduction to practice because he did not produce specific evidence of what he had done and when he had done it. Stating that he took off a certain number of days from his regular employment to work on the laser over a three month period was not enough.

Rule for Diligence through Reduction to Practice: “The party chargeable with diligence must account for the entire period during which diligence is required.” The party must prove what was done and when it was done.

4) Attorney’s diligence:

The court found that the diligence requirement was met where Gould’s attorney took four months during which he was involved in a forty day trial to prepare the application.

5) Corroboration:

His wife’s testimony was insufficient to corroborate Gould’s evidence of his diligence because it was not specific regarding dates and facts. Gould’s notebook was insufficient to corroborate his testimony because it is not enough to show what was done if there is no indication of when it was done.

Disposition:

Affirmed.

Facts: The inventors filed a patent application directed to DNA and cDNA molecules that encoded heparin binding growth factor (HBGF). The examiner rejected the claims as obvious and the Board of Patent Appeals and Interferences affirmed. The examiner cited two prior art references. The Bohlen references provided a partial amino acid sequence of HBGF and did not address the DNA coding of the enzyme. The Maniatis reference disclosed the method of gene cloning that the applicants had used.

Issue: Whether the combination of a prior art reference teaching a method of gene cloning, together with a reference disclosing a partial amino acid sequence of a protein, may render DNA and cDNA molecules encoding the protein prima facie obvious under 35 USC § 103.

Holding: No. In order to establish that a structurally novel chemical compound is prima facie obvious, the teachings of the prior art must suggest the claimed compounds to a PHOSITA (person having ordinary skill in the art).

Reasoning: Obviousness is normally based on structural similarity between the claimed and prior art compounds. Structural similarities may provide a motivation or suggestion to prepare new analogs of known compounds. Such similarities can include geometric or positional isomers or homologs.

In such cases, “the question becomes whether the prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention.” See In re Dillon. Only then does the burden shift to the inventor to rebut the prima facie case of obviousness.

The court held that the prior art did not disclose any relevant DNA molecules or close relatives of the claimed compounds. While the protein sequence was known, the redundancy of the genetic code provided too many alternatives for one to have contemplated or focus on the claimed compounds. One could not have conceived of the sequence until it was isolated and purified and what cannot be contemplated or conceived cannot be obvious. A motivation to search for a gene with a known property does not make the specific gene that is found obvious.

Brief Summary of Holding:

(1) Combination of prior art reference teaching method of gene cloning, together with reference disclosing partial amino acid sequence for a protein that stimulated cell division did not render claims prima facie obvious;

(2) Conceived method of preparing some unidentified DNA does not define it with precision necessary to render it obvious over protein it encodes; and

(3) Patent claims generically encompassing all DNA sequences encoding human and bovine proteins to stimulate cell division were not invalid as obvious.

Disposition: Reversed.

In re Thomas F. DEUEL, Yue-Sheng Li, Ned R. Siegel and Peter G. Milner.

In re Deuel, 51 F.3d 1552, 1558-59, 34 USPQ2d 1210, 1215 (Fed. Cir. 1995).

The Baeyer-Villiger oxidation is a transformation in organic chemistry that inserts an oxygen atom between the carbonyl carbon of a ketone and an adjacent carbon atom:

The reaction is often performed using a peroxyacid such as mCPBA (meta-chloroperbenzoic acid). Other oxidants can be used under certain circumstances including hydrogen peroxide, peroxyacetic acid, peroxytrifluoroacetic acid, and other organic peroxy acids and peroxides.

Mechanism:

The mechanism involves the acid-promoted nucleophilic attack of the carbonyl carbon atom of the ketone starting material by the oxygen atom of the peroxy acid that is not bonded to carbon. This produces the tetrahedral intermediate known as the Criegee intermediate. A pair of electrons on the oxygen atom in the species formed is then used to form a carbon oxygen double bond, and one of the alkyl groups undergoes a 1,2 shift from the carbon atom of the carbonyl to the oxygen atom of the peroxy acid. The carboxylate analog of the peroxy acid is eliminated and the resulting ester product is formed.

Regio- and Stereochemistry:

The regiochemistry and stereochemistry of the reaction products are highly predictable. The group that migrates is the group that is best able to stabilize a developing positive charge in the transition state. Usually, but not always, the more highly substituted group will migrate. If one of the groups is particularly capable of stabilizing a positive charge, such as allyl or benzyl, it will usually migrate even if it is not the most highly substituted group. When the carbon atom that migrates is an asymmetric (i.e. chiral) center, the reaction usually proceeds with retention of configuration.

When aldehydes are subjected to the reaction conditions the hydrogen atom attached to the carbonyl carbon usually migrates and gives rise to the carboxylic acid. If the group attached to carbon is particularly well suited to stabilize a positive charge however, that group may undergo migration to produce the formic acid ester (i.e. formate).

References:

Baeyer, A.; Villiger, V. “Einwirkung des Caro’schen Reagens auf Ketone” (abstract). Ber. 1899, 32 (3): 3625–3633.

Burton, J.W.; Clark, J.S.; Derrer, S.; Stork, T.C.; Bendall, J.G.; Holmes, A.B. “Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin” (Abstract). J. Am. Chem. Soc. 1997, 119 (32): 7483–7498.

M. A. Goodman, M. R. Detty. “Selenoxides as Catalysts for Epoxidation and Baeyer-Villiger Oxidation with Hydrogen Peroxide” Synlett, 2006, 1100-1104.

S. Murahashi, S. Ono, Y. Imada, Angew. “Asymmetric Baeyer-Villiger Reaction with Hydrogen Peroxide Catalyzed by a Novel Planar-Chiral Bisflavin” Chem. Int. Ed., 2002, 41, 2366-2368.

G. A. Olah, Q. Wang, N. J. Trivedi, G. K. S. Prakash. “Baeyer-Villiger Oxidation of Ketones to Esters with Sodium Percarbonate/Trifluoroacetic Acid”, Synthesis, 1991, 739-740.

Michael Renz, Bernard Meunier (1999). “100 Years of Baeyer-Villiger Oxidations”. European Journal of Organic Chemistry 1999 (4): 737–750.

Facts:

Pioneer owned several patents directed to plants and seeds of new varieties of hybrid and inbred corn. When Pioneer sued J.E.M. for infringement, J.E.M. moved for summary judgment on the basis that sexually reproduced plants are not patentable subject matter under 35 U.S.C. § 101. Citing Diamond v. Chakrabarty, the district court denied J.E.M.’s motion and held that 35 U.S.C. § 101 covers plant life and that sexually reproducing plants are patentable subject matter. A unanimous panel of the Court of Appeals for the Federal Circuit affirmed the district court’s decision.

Issue:

Whether sexually reproduced plants and seeds are patentable subject matter within the scope of 35 U.S.C. § 101, despite being unpatentable under the later enacted and more specific Plant Variety Protection Act (PVPA).

Holding:

Yes. Plants are patentable subject matter under both the PVPA and 35 U.S.C. § 101.

Reasoning:

J.E.M. had argued that 35 USC § 101 did not apply to seeds and seed grown plants because Congress intended that they be protected under the Plant Protection Act of 1930 (PPA) and the (PVPA), and that the general statute was superseded by the more specific PVPA.

The Court held that Congress did not intend for the PVPA to exclude new plant varieties from protection under the patent statues. The court held that 35 USC and the PVPA differ in the rights and obligations imposed on a prospective patentee in order to obtain patent protection, but that plants are patentable subject matter under both.

Disposition: Affirmed.

The Friedel-Crafts acylation is an example of an electrophilic aromatic substitution reaction. The overall transformation involves the displacement of an aryl hydrogen atom with an acyl moiety derived from the corresponding acyl chloride. The product of the reaction is an alkyl aryl ketone.

The acyl chloride is first converted to the acylium ion intermediate by reacting it with a Lewis acid catalyst such as aluminum trichloride. The Lewis acid coordinates to the chloride and the activated chloride ion is then eliminated to produce the acylium ion. The acylium ion is now sufficiently electrophilic to undergo nucleophilic attack by the π-system of the aromatic ring. Deprotonation at the aryl carbon that now bears the acyl group restores aromaticity and a neutral charge to the aromatic ring.

The acyl aromatic compound produced by the Friedel-Crafts acylation can undergo a number of different transformations and functional group manipulations. The carbonyl moiety can be reduced to a methylene by means of either the Clemmensen Reduction or the Wolff-Kishner Reduction. This sequence of reactions is formally equivalent to the Friedel-Crafts alkylation but does not suffer from the same problems such as carbocation rearrangements and polyalkylation.

The Friedel-Crafts alkylation reaction is related to the acylation in that both reactions are electrophilic aromatic substitution reactions and both employ aluminum trichloride to activate an organohalide. The starting material for the alkylation is an alkylhalide and the reaction introduces an alkyl group to the aromatic ring. See the synthesis of 1,1-diphenylacetone for an example of the laboratory procedure for this reaction.

The Finkelstein reaction involves the reaction of an alkyl chloride or bromide with sodium iodide to produce the corresponding alkyl iodide. The reaction may proceed via either an S_N1 or S_N2 mechanism depending on the nature of the alkyl halide.

Mechanism:

Acetone is employed as solvent in the classical version of the reaction. Acetone is used in order to take advantage of the relatively higher solubility of sodium iodide compared to sodium bromide or chloride. The precipitation of the chloride or bromide salts removes the ions from solution and drives the reaction to completion. In the synthesis of ether compounds, the reaction can be used to prepare a suitable alkyl iodide for use in the Williamson Ether Synthesis.

The reaction can also be performed in other solvents and the reaction can be driven to completion by the addition of a large excess of iodide. The reaction can also be employed using a catalytic amount of iodide. The alkyl iodide product can be generated in situ where it reacts further, regenerating the iodide.

The relative rates of reactivity of various alkyl halides in the Finkelstein reaction resembles the rates of reactivity observed in other nucleophilic substitution reactions. The reaction rate increases as the number of carbons bonded to the carbon atom bearing the halogen decreases. The reaction rate is significantly higher when the carbon atom that undergoes attack is adjacent to a double bond or aromatic ring. Allyl bromide and benzyl bromide have a much higher rate of reaction than simple primary alkyl halides such as ethyl bromide. Electron donors on such double bonds or aromatic rings tend to increase the rate of reaction. Electron withdrawing groups tend to decrease the rate. This is consistent with a transition state that places a developing positive charge on the carbon atom undergoing attack.

One variant of the reaction involves converting an alcohol to an excellent leaving group such as a tosylate, and then converting the tosylate to the iodide. This sequence formally has the effect of converting an alcohol to an alkyl halide.

Experimental Procedure:

For an example of the laboratory procedure for the Finkelstein reaction, see the synthesis of ethyl 5-iodovalerate.

References:

H. Fickelstgein, Ber., 1910, 43, 1528.

C. K. Ingold, Structure and Mechanisms in Organic Chemistry (Cornell Univ. Press, London, 2nd ed., 1969) p. 435.

Streitwieser, A. Chem. Rev., 1956, 56, 571.

J. Hayami et al., Tetrahedron Letters, 1973, 385.

S. Samaan, F. Rolla, Phosphorus and Sulfur, 4, 145 (1978).

W. B. Smith, G. D. Branum, Tetrahedron Letters, 1981, 22, 2055.

F. G. Bordwell, W. T. Brannen, J. Am. Chem. Soc., 1964, 86, 4645.

D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68, 4281-4285.

T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004, 60, 10943-10948.

Maloney, D. J. Hecht, S. M. Org. Lett., 2005, 7, 4297.

The Dieckmann Condensation is an intramolecular variant of the Claisen Condensation. The reaction is most commonly used to prepare 5 or 6 membered ring ß-keto esters. The formation of 5 membered rings tends to be faster than 6 membered rings, although the 6 membered ring products are generally more thermodynamically stable. Ring formation becomes progressively more difficult to accomplish as the ring size of the desired product increases.

The reaction typically employs the sodium alkoxide of the alcohol that corresponds to the alcoholic moiety of the ester functional groups. The reaction can also be promoted by the use of one equivalent of sodium hydride and a catalytic amount of the corresponding alcohol.

The Dieckmann Condensation generally cannot be used to prepare small, highly strained ring systems. Rather than form a three membered ring, diethyl succinate undergoes an intermolecular Claisen Condensation followed by a Dieckmann Condensation to afford the six membered ring compound instead of reacting to form the three membered ring ß-keto ester as shown below.

See 3-quinuclidone hydrochloride for an example of a laboratory procedure for the Dieckmann condensation.

References:
Dieckmann, W. Ber., 1894, 27, 102, 965.
Dieckmann, W. Ber., 1900, 33, 595, 2670.
Dieckmann, W. Ann., 1901, 317, 51, 93.
Schaefer, J.P.; Bloomfield, J.J. Org. React., 1967, 15, 1-203.
J. Org. Chem., 1998, 63, 4069-4078.
T. R. Hoye, V. Dvornikovs, E. Sizova, Org. Lett., 2006, 8, 5089-5091.
Davis, B. R.; Garrett, P. J. Comp. Org. Syn. 1991, 2, 806-829. (Review)
Janice Gorzynski Smith. Organic Chemistry: Second Ed. 2008. pp 932-933.

In re Brana, 51 F.3d 1560 (Fed. Cir. 1995).

Facts:

Brana filed a patent application directed to antitumor compounds. The compounds were very similar to other known antitumor compounds but had not been tested in human subjects. The known compounds had been evaluated using a computer test that was used to identify compounds as candidates for further testing by the National Cancer Institute. The National Cancer Institute then performed in vitro tests for antitumor activity against human tumor cells, and in vivo tests for efficacy against two lymphatic leukemias in mice. The patent application pointed out the similarity between the claimed compounds to the known antitumor compounds and demonstrated the cytotoxicity of the compounds against human tumor cells in vitro.

The examiner rejected the application on the grounds that the application failed to specify a specific disease against which the compounds were effective, and because the test results were insufficient to establish that there was a reasonable expectation that the compounds had a practical utility. On appeal, the Board of Patent Appeals and Interferences affirmed the examiner’s rejection.

Issue: The issue is what the applicant must prove regarding the practical utility or usefulness of pharmaceutical inventions.

Holding: The court held that while the examiner’s rejection and the Board of Patent Appeals and Interferences decision appeared to be based on the issue of whether the compounds had a practical utility, the real issue pertained to the requirements for patentability under 35 USC 112 p 1. The court considered two issues.

Specific Utility:

The first basis for the Board’s decision was that the application had failed to disclose that the compounds were active against a specific disease and that one of ordinary skill in the art would be unable to use the invention without undue experimentation. (See Hybritech Inc. v. Monoclonal Antibodies, Inc.)

The court held that the applicants’ favorable comparison to the compounds with known activity implicitly asserted that the claimed compounds were highly effective against lymphocytic leukemia and therefore useful. In light of the comparison to the known compounds, the court held that the specification alleged a sufficiently specific use. The court held that while the tumors were man made, they nevertheless represented real tumors and it was unnecessary to wait for them to occur naturally.

Utility:

The Board also affirmed the rejection of the claims on the basis that even if the specification disclosed a specific utility, the application did not prove that the claimed compounds are useful. The court held that the PTO has the initial burden to make a prima facie showing that the invention lacks utility. The PTO must challenge the application’s presumptively correct utility disclosed in the application. Only after the PTO has provided evidence that one of ordinary skill in the art would reasonably doubt the asserted utility does the burden shift to the applicant to provide evidence sufficient to convince such a person of the invention’s asserted utility. The court found that the PTO failed to make a prima facie showing that the invention lacked the asserted utility and that the applicants should not have been required to substantiate their disclosure to avoid the rejection. The court also found that even if the PTO had meet this initial burden, the applicants submitted sufficient evidence to convince one of skill in the art of the asserted utility. The court noted that the requirements to obtain the approval to market a drug are not the same as the requirements to obtain a patent. The court stated that

[u]sefulness in patent law, and in particular in the context of pharmacological inventions, necessarily includes the expectation of further research and development. The stage at which an invention in this field becomes useful is well before it is ready to be administered to humans. Were we to require Phase II testing in order to prove utility, the associated costs would prevent many companies from obtaining patent protection on promising new inventions, thereby eliminating an incentive to pursue, through research and development, potential cures in many crucial areas such as the treatment of cancer.

The court also reaffirmed that proof of an alleged pharmaceutical property for a compound through statistically significant tests using standard laboratory animals is sufficient to establish utility. Namely, one who has taught the public that a compound exhibits some desirable pharmaceutical property in a standard laboratory animal has made a significant and useful contribution to the art, even though it may eventually appear that the compound is without value in the treatment of humans. (See In re Krimmel.)

Disposition: Reversed.