HOW CAN THE CHEMIST HELP THE PATENT LAWYER THE PHARMACEUTICAL CHEMIST AND THE PATENT LAWYER* By L. D. DIBBLE Adams, Forward and McLean, 425 Thirteenth St., N.W., Washington 4, D.C.
In the pharmaceutical f i e l d like the chemical field and other f i e l d s , t h e r e a r e many ways i n which the chemist can help the patent l a w y e r , including accumulation of data f o r the specification, help a t interviews with the E x a m i n e r , checking opponents' applications f o r adequacy and operability in i n t e r f e r e n c e s , & This c a l l s f o r cooperation and t e a m play. How best t o get this a l l impurtant co-operation and t e a m p l a y ? Possibly the G e r m a n s y s t e m o r amodification of the G e r m a n S y s t e m is the a n s w e r . Under the G e r m a n S y s t e m , as explained t o m e , the law provides f o r the payment of money to the c h e m i s t inventor in the event h i s invention is patented and is used c o m m e r c i a l l y . The amount of paywhich is o v e r and above h i s basic s a l a r y , ment if an employee, f o r e x a m p l e , of a corporation is not s e t but i s negotiated with the corporation when the invention goes c o m m e r c i a l . With this incentive s y s t e m t h e r e is l i t t l e doubt but that the chemist-inventor would supply the r e q u i r e d cooperation. If the s y s t e m was modified to cut the attorney who p r e p a r e d the patent in on the loot when the invention goes c o m m e r c i a l , t h e r e is a l s o little doubt about the r e q u i r e d t e a m play. The p r e s e n t G e r m a n S y s t e m where the chemist-inventor alone gets the m o n e t a r y r e ward however, h a s its disadvantages. One of t h e s e was pointed out to m e by D r . G e r h a r d t I r m i s c h of F a r b e n w e r k e Hoechst, who stated that h i s company was having a v e r y difficult t i m e getting patent a t t o r n e y s f o r t h e i r Patent Departm e n t , a s the people with the scientific background r e q u i r e d by the Patent Department all wanted to work i n the l a b o r a t o r y where they invent, k., would have a chance at the j a c k p o t provided under the G e r m a n law. The t e r m "jack pot" is used in i t s t r u e s e n s e and can be i l l u s t r a t e d by the o r a l anti-diabetic, O r i n a s e , sold byThe Upjohn Co. under a l i c e n s e f r o m Hoechst. The annual s a l e s of t h i s product in t h i s country alone a r e r u m o r e d to r u n around $25,000,000, In the pharmaceutical field, t o provide a b a s i s f o r cooperation and t e a m play between the chemist-inventor and the l a w y e r i t h a s been found worthwhile, if not e s s e n t i a l , f o r the l a w y e r to educate o r acquaint the c h e m i s t with the r e q u i r e m e n t s of patentable subject m a t t e r in t h i s field. This education need not be and should not be involved. T h e r e a r e only t h r e e basic r e q u i r e ments: novelty, utility and unobviousness. Novelty.-To be patentable the subject m a t t e r , product o r p r o c e s s , m u s t be new-the novelty can be thin but i t m u s t be t h e r e . When a chemical compound is named in a p r i o r publication the novelty is gone. This applies even when a n
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investigator r e p o r t s , e.g. i n the J. A. Chem. all a t t e m p t s r m a k e the compound failed. A l a t e r investigator working f o r s a y seven y e a r s , who successfully m a k e s the c o m pound and finds that it will c u r e c a n c e r , m a y be entitled to a patent on the p r o c e s s of making the compound o r even a L a s k a r Award o r the Nobel Prize-but the compound p e r s e is unpatentable. The investigator finding that the compound would c u r e c a n c e r , however, can under the new statute protect his discovery by obtaining a patent on the u s e of the compound f o r that purpose. This was done recently by Burroughs Wellcome & Co., i n T i m m i s patent 2,917,432 entitled L e u k e m i a T r e a t m e n t . In t h i s c a s e the compound used, 1,4-dimethanesulphonyloxybutane w a s old, but i t s u s e i n the control of a type of l e u k e m i a w a s new. The T i m m i s c l a i m , in p r o c e s s f o r m , as i t m u s t be under the s t a t u t e , r e a d s as follows: A p r o c e s s f o r producing r e m i s s i o n s i n patients suffering f r o m chronic myeloid leukemia which c o m p r i s e s a d m i n i s t e r i n g 1,4-dimethanesulphonyloxybutane to a patient afflicted with the d i s e a s e . Thi's type of "use p r o c e s s " c l a i m , which involves the t r e a t m e n t of a d i s e a s e , is relatively new and many l a w y e r s initially did not believe c l a i m s of t h i s type of m u c h r e a l value They p r e s e n t p r o b l e m s , which we do not have t i m e t o d i s c u s s h e r e , but m o s t l a w y e r s working i n the pharmaceutical field a g r e e today that they a r e of value. Illustrative examples a r e the HoffmannLaRoche F o x R e - i s s u e patent 23,947 involving the u s e of the old chemical compound, isonicotinic acid hydrazide , f o r combatting t u b e r c u l o s i s , and the Wisconsin Alumni R e s e a r c h Foundation's (WARF) Link, e t . . , patent 2,601,204 involving the u s e of the old compound 3,3'-methylenebisas Dicumarol, as ( 4 - h y d r o x y ~ o u m a r i n known )~ a blood anticoagulant f o r preventing additional i n t r a v a s c u l a r c l o t s , o r a s the m e d i c a l people p r e f e r , a s a prophylaxis of f u r t h e r t h r o m b o e m bolic episodes. This is on the a s s u m p t i o n that you a r e i n a position f o r a second episode, i.e., a r e alive a f t e r the f i r s t c o r o n a r y . It is i n t e r e s t i n g to note that both HoffmannLaRoche, along with Squibb, f o r t h e i r w o r k with isonicotinic acid h y d r a z i d e , and Dr. Link, f o r h i s work with Dicumarol, r e c e i v e d L a s k a r Awards i n the s a m e y e a r . It is a l s o i n t e r e s t i n g to note that the M e r c k Index s t a t e s that Dicumarol was f i r s t isolated f r o m spoiled sweet clover by Link, e t . This i s c o r r e c t a s far as isolation f r o m clover is concerned, and i t took Link, e t . , seven y e a r s to complete t h i s w o r k , but the f i l e h i s t o r y of the Link,e%., patent will show that Dicumarol was f i r s t r e p o r t e d in the G e r m a n
SOC.that
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*Presented before he Division of Chemical Literature, ACS National Meeting, New York, September 12, 1960.
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THE PHARMACEUTICAL CHEMIST AND THE PATENT LAWYER
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literature with a n i n c o r r e c t m e l t i n g point about 50° off, and with no r e f e r e n c e t o i t s p r o p e r t i e s o r possible u s e . T h i s old G e r m a n r e f e r e n c e , while it did not contribute anything w o r t h while, w a s a d e q u a t e , h o w e v e r , t o d e s t r o y novelty, and it is f o r this r e a s o n that the Link, e t a l . , p a t e n t d o e s not c l a i m D i c u m a r o l p e r s e . T h i s patent with i t s p r o c e s s u s e c l a i m s is n e v e r t h e l e s s a valuable patent and the r o y a l t i e s paid by the F o u n d a t i o n ' s l i c e n s e e s , Abbott L a b o r a t o r i e s and E l i Lilly & Co., a r e substantial today. Summarizing a s to novelty the c h e m i s t c a n a s s i s t the l a w y e r by pointing up the noveltyand if novelty d o e s not e x i s t by forgetting about the subject m a t t e r patentwise. Utility.-To be patentable the subject m a t t e r m u s t be useful, ifi, have a u s e and the u s e m u s t be disclosed. HeTe a g a i n the u s e can be thinbut it m u s t be t h e r e . If the compound is a n i n t e r e s t i n g i n t e r m e d i a t e of no known u s e but of possible u s e it still i s not patentable. The C o u r t of C u s t o m s and A p p e a l s , r e c e n t 3 to 2 d e c i s i o n in C i b a ' s In r e Nelson c a s e , involving the utility of s t e r o i d i n t e r m e d i a t e s , d o e s not change t h i s basic r e q u i r e m e n t . T h e utility a s noted above c a n be thin-that i s , it d o e s not n e c e s s a r i l y have to be c o m m e r c i a l o r the hoped f o r utility in the m e d i c a l field. An i l l u s t r a t i v e e x a m p l e i s the Hoffmann-LaRoche A m e r i c a n C a n c e r Society's f l u o r o u r a c i l patent. T h i s p r o d u c t w a s p r e p a r e d and i n t e s t s on a n i m a l s showed !some a n t i - t u m o r activity. At the t i m e the application w a s filed activity i n h u m a n s had not been d e m o n s t r a t e d and, a s fluo r o u r a c i l a l s o hats s o m e a n t i b a c t e r i a l p r o p e r t i e s , the utility d i s c l o s e d in the patent is i n the antib a c t e r i a l field. R e c e n t clinical w o r k a t NIH h a s c o n f i r m e d the a n i m a l t e s t s and shown f l u o r o u r a c i l t o have u s e i n the t r e a t m e n t of c e r t a i n types of t u m o r s . Another exainple i s a new product found in a n i m a l t e s t s to be effective a g a i n s t S a r c o m a 180, C a r c i n o m a 755 and in 13 other different types of t u m o r s by Sloan-8Kettering Institute f o r C a n c e r . R e s e a r c h , and c o n f i r m e d i n o t h e r l a b o r a t o r i e s . In t h e s e t e s t s , the product i s r e p o r t e d by the C a n c e r C h e m o t h e r a p y National S e r v i c e C e n t e r to h a v e the greatest: s p r e a d in c o n c e n t r a t i o n r e q u i r e d f o r effective action against t u m o r s and the toxic c o n c e n t r a t i o n of any a n t i t u m o r agent yet isolated and t e s t e d . However, as clinical data w e r e l a c k i n g at the t i m e the initial application w a s f i l e d and, a s the product had antifungal a c tivity a g a i n s t ordlinary a i r borne m o l d s , the utility d i s c l o s e d in the initial application w a s in the antifungal field -- with s p e c i a l r e f e r e n c e to i t s u s e i n l a b o r a t o r y b a c t e r i a l c u l t u r e s to p r e v e n t contamination by m o l d s . The r e f i l e application d i s c l o s e s the a n t i - t u m o r p r o p e r t i e s a s the p r o d uct w a s about t o go under and i s now under clinic a l t e s t a t NIH. We should have the a n s w e r , one way o r the o t h e r , , soon.
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Still a n o t h e r example is coenzyme Q, r e p o r t e d in the l i t e r a t u r e by D r . David G r e e n and h i s a s s o c i a t e s a t the Enzyme Institute a t the U n i v e r s i t y of Wisconsin and by D r . K a r l F o l k e r s and h i s g r o u p at M e r c k . Coenzyme Q i s a n e x t r e m e l y i n t e r e s t i n g new type of tetrasubstituted benzoquinone. One substituent i s a methyl g r o u p , two a r e methoxy groups and the f o u r t h i s a long u n s a t u r a t e d chain m a d e of i s o p r e n o i d g r o u p s . The compound i s of i n t e r e s t in the m e d i c a l field a s i t i n a way r e s e m b l e s v i t a m i n K. The utility, h o w e v e r , given f o r coenzyme Q in the patent application, a s c e r t a i n a b l e by a look a t the e a r l y issuing f o r e i g n c a s e s , is u s e a s a l a b o r a t o r y tool f o r a s s a y i n g f o r the p r e s e n c e of or amount of succinic acid o r the succinate r a d i c a l . Obviously, this i s not a c o m m e r c i a l u s e but it i s adequate to m e e t the utility r e q u i r e m e n t . If the utility a s s e r t e d in the application i s m e d i c a l , s u c h a s a n t i t u m o r p r o p e r t i e s a s in the above r e f e r r e d r e f i l e c a s e , the therapeutic utility, including showings that the product i s s a f e , e f fective and r e l i a b l e f o r i t s intended p u r p o s e , m u s t be thoroughly documented by clinical d a t a , with m e d i c a l publications by independent medical i n v e s t i g a t o r s being v e r y helpful f o r this purpos The r e a s o n f o r extensive showings h e r e i s that and the C o u r t s recognize the P a t e n t Office that s o m e m e m b e r s of the public a r e likely to r e l y on the g r a n t of a U. S. patent a s certifying t o the s a f e n e s s , reliability and effectiveness of the patented m e d i c i n e , Summarizing as f o r utility the c h e m i s t c a n a s s i s t the l a w y e r by pointing up utilit); and, i f no known utility e x i s t s , by forgetting about the subject m a t t e r patentwise until s o m e utility h a s been d e m o n s t r a t e d . Unobviousness .-Even if novelty and utility a r e p r e s e n t , a patent still m a y not be obtained if the subject m a t t e r sought to be patented would have been obvious a t the t i m e the invention was m a d e to a p e r s o n having o r d i n a r y skill in the a r t . It would be well f o r the c h e m i s t - i n v e n t o r to k e e p this in mind when reviewing p r i o r publications, o r what the l a w y e r c a l l s , the p r i o r a r t . I have s e e n m a n u s c r i p t s which r e v i e w p r i o r a r t publications 10-15 y e a r s old, and then s t a t e in substance that this a r t points to and obviously s u g g e s t s the work r e p o r t e d in the m a n u s c r i p t . A s s u m i n g other investigators w e r e not a s l e e p a t the switch, the g a p of 10-15 y e a r s , or e v e n 10 y e a r s o r l e s s , between the p r i o r publications and the w o r k r e p o r t e d in the m a n u s c r i p t c l e a r l y negatives o b v i o u s n e s s , a t l e a s t to a l a w y e r . S u m m a r i z i n g , the c h e m i s t c a n a s s i s t the l a w y e r if he will point up why the subject m a t t e r sought t o be patented is not obvious. All of the above r e l a t e s to factual data and the d i s c l o s u r e in the specification, and not the c l a i m s . C l a i m drafting in m o s t instances involves technical p r o b l e m s with which the l a w y e r alone should be c o n c e r n e d .
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My job personally h a s been made relatively e a s y by acquainting the people with whom I work with the basic r e q u i r e m e n t s of novelty, utility and unobviousness noted above. In P r o f e s s o r Link's l a b o r a t o r y , f o r e x a m p l e , the graduate and post-graduate students p r e p a r e invention d i s c l o s u r e s with detailed examples which can be dropped into the specification without change. This training should be of aid to l a w y e r s when t h e s e students go out into i n d u s t r y . In the State of Michigan, Department of Health, the investig a t o r s work i n the antibiotic field. After working out the f o r m of what the Patent Office d e s i r e d f o r a complete antibiotic specification, the invention d i s c l o s u r e s now come to m e i n the f o r m of the approved specification with complete d a t a . and a l s o m a t e r i a l l y This is of enormous help cuts down the b i l l s , Up to now we have been considering what the c h e m i s t should o r should not do. I would like to close with a word about the lawyer who, like the c h e m i s t , h a s h i s place o r position to play in the game requiring cooperation and t e a m w o r k . The lawyer should not t r y to take over the c h e m i s t - i n v e n t o r ' s job o r the r e s p o n s i b i l i t i e s of the D i r e c t o r of R e s e a r c h o r a t t e m p t to r u n the company f o r management. Also, unless the lawyer can predict better than I have been able to do, the lawyer should not evaluate or e s p e cially r u n down the c o m m e r c i a l a s p e c t s of the c h e m i s t ' s invention. This can d e s t r o y c o o p e r a tion and any possible t e a m play. I close with this illustration, where I batted z e r o . When K a r l P a u l Link d i s c o v e r e d w a r f a r i n , another 4-hydroxycoumarin anticoagulant, and with Ward R o s s , managing d i r e c t o r of WARF, went out to s e l l w a r f a r i n a s a multi-dose r o denticide, I had m y doubts. I was not alone-the P r e s i d e n t s of the two l a r g e s t companies in t h i s field went on r e c o r d and s a i d i t would not work. Their doubts, like m i n e , w e r e based on the c r i t i c a l multiple d o s e a s p e c t . L e t m e illustrate.
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this as follows. If a r a t e a t s 10 m g . of w a r f a r i n at one t i m e , t h e r e is no toxic effect. On the other hand, if a rat e a t s 1/10 as much-say 1-1.5 m g . , over a 3-4 day period, f o r example, 1 / 3 m g . p e r day f o r 4-5 days-the rat will die. That D r . Link was right, is c l e a r l y evidenced by the f a c t that WARF's l i c e n s e e s i n the r o denticide field have paid the Foundation substantial r o y a l t i e s -running into the millions and w a r f a r i n rapidly became and still is the l e a d e r i n the rodenticide field throughout the world, When Dr Link then proposed that the sodium derivative, o r salt, of the well established r a t poison, w a r f a r i n , be used on humans, in the clinic, as the d r u g of choice f o r the prophylaxis of thrombo-embolic episodes-I r e a l l y had m y doubts. H e r e again I was not alone-the leading clinicians in G r e a t Britain and s o m e here-but not the A m e r i c a n H e a r t Association-went on r e c o r d , and said they would not p r e s c r i b e rat poison t o t h e i r patients. Once again, D r . Link was r i g h t , and my doubts proved not to be well founded, as i l l u s t r a t e d by the f a c t that the r o y a l t i e s paid to the Foundation f o r clinical w a r f a r i n sodium, a r e l a r g e r than those paid under the well established Dicumarol patent. Also, the w a r f a r i n sodium used in the clinic l a s t y e a r , 1959-if made into s t a n d a r d r a t bait-would make 2 , 0 0 0 , 0 0 0 pounds of bait-and if this bait w e r e eaten by r a t s - - i n the amount to kill--and no m o r e ( r a t s o r d i n a r i l y consume a n overdosage)-it w o u l d k i l l over 200,000,000 r a t s . That is a lot of dead r a t s , and yet t h e r e h a s been no r e p o r t of the l o s s of any patient f r o m the a d m i n i s t r a t i o n of w a r f a r i n sodium in the clinic. Finally-as to the drug of choice-proposed by D r . Link-if we a s s u m e that the P r e s i d e n t ' s physicians-President E i s e n h o w e r ' s d o c t o r s after his coronary-would p r e s c r i b e the best clinical anticoagulant available-then Dr Link was right-warfarin sodium is the drug of choice.
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