Predicting Synergy

Many US practitioners were shaken by the Supreme Court’s establishment of an “obvious to try” rationale for obviousness in KSR v Teleflex:

“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.” (Emphases added)

On June 18, 2013 the Court of Appeals of the Federal circuit (CAFC) decided NOVO NORDISKA/S INC. V CARACO PHARMACEUTICAL LABORATORIES LTD. [Opinion]

The case was an appeal to the CAFC by NOVO following a finding of obviousness by the district court for the Eastern District of Michigan which held that claim 4 of U.S. Patent No. 6,677,358 was obvious in litigation stemming from an ANDA (abbreviated new drug application)  filed by Caraco. At issue was whether secondary considerations relating to unexpected results render a claim non-obvious. (The case also dealt with inequitable conduct using the standards established in Therasense, but this posting will relate only to the obviousness issues)

Claim 4 of US 6,677,358, is directed towards a combination therapy for diabetes:

A method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin.

The claim recites two active ingredients repaglinide and metformin, used in combination. Each of these active ingredients was previously known as an anti-diabetic medication and the issue to be resolved was whether the combination is obvious in the sense of § 103.

Repaglinide is an insulin secretagogue of the meglitinide class.  Insulin secretagogues stimulate insulin release from the pancreas.  Insulin secretagogues include sulfonylureas as well as meglitinides. At the filing date of US 6,677,358 there were fifteen known secretagogues of which five were in the meglitinide class. Repaglinide is a rapid and short-acting insulin secretagogue that is quickly eliminated from the body.

Metformin is an insulin sensitizer which acts on the liver to reduce glucose production, thereby improving insulin sensitivity in muscle and fat tissues. At the relevant time, metformin was the main insulin sensitizer in use.

 Novo initiated a study in Australia, conducted by Dr. Moses, in which patients that did not respond well to metformin monotherapy were given a repaglinide/metformin combination. The Moses study indicated that this combination reduced glycosylated hemoglobin 1.41%, roughly double the effect observed with either drug administered separately. The Moses study also measured fasting plasma glucose (FPG) and revealed that the repaglinide/metformin combination reduced FPG to levels eight times lower than those typically observed with metformin alone.  This was surprising because repaglinide is known to be short acting, and was not previously believed to affect FPG.

Based upon the results of the Moses study, Novo filed a patent application. Claims in that application were rejected by the Examiner who reasoned that “…it was obvious to try combining repaglinide with metformin, and it was also predictable that the combination would yield, at a minimum, a benefit equal to the drugs taken separately, i.e., an “additive” effect.”

No progress was made in prosecution until Novo presented a declaration from Dr. Sturis which contained results of an additional study.

Dr. Sturis’s study tested the effects of metformin and repaglinide on the glucose levels of “Zucker obese rats,” which are rats bred specifically for use in pharmaceutical studies as models for obesity, diabetes and heart disease. Dr. Sturis divided twenty rats into four groups:

the first group was given a placebo;

the second was given only metformin;

the third was given only repaglinide; and

the fourth was given the repaglinide/metformin 

combination therapy. 

Dr. Sturis measured the blood glucose levels of these rats at 30, 60, and 120 minutes,  and  then calculated the combination’s “hypothetical additive effect” by adding the glucose reduction found in the metformin-only rats to that of the repaglinide-only rats. 

Dr. Sturis then compared the “hypothetical additive effect” to the actual glucose reduction found in the repaglinide/metformin group to calculate the probability (as a “p-value”) that any glucose reduction caused by the combination therapy might be attributable to synergistic rather than additive effects.

He reported the results in two ways. First, he plotted a chart showing glucose levels across time and then calculated the “area under the curve” for each line, thus expressing the average glucose reduction found across the entire study for each group of rats. According to this calculation, the rats who received the repaglinide/metformin treatment experienced a greater average reduction in blood glucose levels than the other three groups, and the combination therapy also proved more effective than the “hypothetical additive effect” of the two drugs. The p-value for this finding was 0.061.  Second, Dr. Sturis analyzed the glucose measurements at 120 minutes mark and found the largest disparity between repaglinide/metformin and the other three groups. Using the 120 minute data alone, he calculated a p-value of 0.02.

In his declaration, Dr. Sturis opined that the 0.061 p-value “indicate[d]”  that repaglinide/metformin had a synergistic effect upon blood glucose levels over the entire two-hour span, and that the 0.02 p-value at the 120-minute mark in particular demonstrated “significant synergy.” His conclusion was that repaglinide/metformin combination therapy had synergistic effects in Zucker obese rats, and that his study, together with the Moses Study “strongly suggest[ed] that the combination of repaglinide and metformin has synergistic properties in type 2 diabetic [human] patients.”

In submitting this evidence, Novo’s counsel asserted that the declaration provided “clear evidence of synergy…in the treatment of type II diabetes.”  In the opinion of Novo’s counsel, any prima facie case of obviousness was “rebutted by the evidence of synergistic and surprising results achieved by the claimed combined therapy in humans.”

The Examiner withdrew the obviousness rejection based upon these submissions.

To this point, this posting has been a summary of the facts presented in the first few pages of the court decision.

Now let’s look at these facts in the context of the KSR “obvious to try” rationale.

Was there “market pressure to solve a problem”?  Yes, some patients did not respond well to metformin monothereapy.

Were there a finite number of identified… solutions? Yes, there were fifteen known secretagogues of which five were in the meglitinide class and 10 were sulfonylureas.

Now comes the hard question, were these solutions “predictable”?  The answer here depends on what is meant by predictable.

One of ordinary skill would probably have predicted that each of the fifteen known secretagogues, including each of the five meglitinides, would have at least an additive effect when combined with metformin. That assertion seems consistent with the way that Dr. Sturis calculated his “hypothetical additive effect”.

However, one of ordinary skill might not have predicted that any of the fifteen known secretagogues would produce an eightfold reduction in FPG as repaglinide did in the Moses study.

Now we return to the CAFC decision and its analysis of the lower court finding of obviousness.

In the initial trial, both parties agreed that Caraco established a prima facie case that it was obvious to try combination therapy using metformin and repaglinide to treat Type II diabetes. This is because it was well known that two drugs having different mechanisms for treating diabetes can be more effective than one, and so drugs were often tested in combination therapy after demonstrating effectiveness in monotherapy. In fact, combination therapy using insulin sensitizers and insulin secretagogues was common at the time, and metformin was the most widely-used insulin sensitizer at the relevant date.

The district court viewed this as a prima facie case for obviousness and then went about analyzing “the evidence and assertions of unexpected and surprising results, as well as synergistic results.”  The lower court focused on the question of whether the reported synergy was unexpected.

Caraco submitted new prior art as well as testimony from expert witnesses and Novo scientists. Upon review of Caraco’s evidence, the district court determined that one of ordinary skill would have expected some synergy from the repaglinide/metformin combination. The district court did not find that the two studies proffered by Novo were sufficient to establish an unexpected or superior level of synergy. Instead the lower court found that the results presented by Novo were entirely expected based upon the state of the art. The district court finally concluded that Caraco had provided “clear and convincing” evidence of obviousness of claim 4.

The CAFC reviews all of the arguments and, in the end, upholds the district court ruling of obviousness. In this specific case, that is not surprising (despite a well reasoned and thorough dissent from Judge Newman).

What is surprising, is the implication that if an extraordinary amount of synergy is observed, a combination may be patentable, even if there were only a finite number of solutions which might have been predicted to work in a less dramatic fashion. Perhaps this makes the “obvious to try” rationale established by KSR less troubling.

Time is on your side

One of the most helpful concepts in contemplation of legal opinions is “Everything I know is wrong.” That is because logic which appears infallible in a non-legal context is often at odds with the law’s own internal logic. Often, but not always.

On August 12, 2013 the Court of Appeals of the Federal circuit (CAFC) decided LEO PHARMACEUTICAL PRODUCTS, LTD. v TeresaStanek Rea, ACTING DIRECTOR (USPTO) [Opinion]

The case was an appeal to the CAFC by LEO following a finding of obviousness by the Board of Patent Appeals and Interferences (BPAI) of the USPTO during inter partes re-examination of U.S. Patent No. 6,753,013. The ‘013 patent has a priority date of Apr 23, 1999.

Claim 1, despite it’s length, is relatively simple (emphases added):

1.  A pharmaceutical composition for dermal use, said composition comprising:

a first pharmacologically active component A consisting of at least one vitamin D analogue selected from the group consisting of seocalcitol, calcipotriol, calcitriol, tacalcitol, maxacalcitol, paricalcitol, falecalcitriol,  1α,24S-dihydroxy-vitamin D2,

1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-secopregna-5(Z),7(E),10(19)-triene and mixtures thereof; and

a second pharmacologically active  component B consisting of at least one corticosteroid,

wherein the difference between the maximum stability pH of said first component A and the maximum stability pH of said second component B is at least 1; and

at least one solvent component C selected from the group consisting of:

(i) compounds of the general formula R3(OCH2C(R1)H)xOR2 (I) wherein x is in the range of 2-60, R1in each of the x units is CH3, R2is straight chain or branched C1-20 alkyl or benzoyl, and R3 is H or phenylcarbonyloxy;

(ii) straight or branched C2-4-alkyl esters of straight or branched C10-18-alkanoic or -alkenoic acids;

 (iii) propyleneglycol diesters with C8-14-alkanoic acids; and

(iv) branched primary C18-24 alkanols,

wherein said pharmaceutical composition is storage stable and non-aqueous.  

In non-legal terms this means that the claimed invention is a composition including at least one vitamin D analogue and at least one corticosteroid in  at least one solvent. The entire composition must be storage stable and non-aqueous despite the fact that the difference between the maximum stability pH of the vitamin D analogue and the maximum stability pH of the corticosteroid differ by at least 1. The solvent described as an embodiment in the ‘013 patent is  Polyoxyproplyene 15 Stearyl Ether (POP-15-SE).

The claimed composition is useful in the treatment of skin conditions such as psoriasis.

It was previously known  that both vitamin D analogues and corticosteroids were useful in the treatment of these skin conditions. However, the two ingredients were traditionally administered separately (e.g. one in the morning and the other in the evening).

The BPAI concurred with the Examiner that the claims were obvious according to § 103 in view of: US 4,083,974 (Turi);US 4,610,978 (Dikstein); and WO 94/13353 (Serup) in various combinations.

The CAFC considered whether the various combinations of the three reference would have been obvious to make.

Here are the facts as the CAFC explains them:

Turi, filed in 1977, discloses pharmaceutical compositions comprising a steroid contained within a

solvent, POP-15-SE, but does not teach the use of vitamin D. Turi discloses the use of POP-15-SE as “well known to those skilled in the art of formulating and compounding topical ointment like compositions and preparations.” Turi specifically discloses that the claimed invention does not contain water, gels, or alcohols. Turi addresses neither stability concerns from combining vitamin D analogs and corticosteroids, nor the use of POP-15-SE or corticosteroids for the treatment of psoriasis.

Dikstein, filed in 1984, discloses dermatological compositions, including creams, ointments, and lotions, comprising a vitamin D analog and a corticosteroid. Dikstein teaches that vitamin D can treat psoriasis and that corticosteroids have side effects, but it does not teach using vitamin D to treat the side effects of corticosteroids. Every example composition in Dikstein contains almond oil or propylene glycol and several also contain water. Dikstein does not disclose or recognize the storage stability problems associated with using water, almond oil, or propylene glycol in the combination formulations. Nor does Dikstein disclose the use of POP-15-SE or any other solvent that could solve the storage stability concerns.

Serup, filed in 1993, describes a composition containing a vitamin D analog and a steroid and teaches the use of vitamin D analogs  to treat skin atrophy, a well-known side effect of steroid treatment. Although Serup describes the benefits of using vitamin D to treat steroid-induced atrophy, Serup does not address any storage stability concerns associated with this combination.  While Serup teaches that preparations may include “creams, ointments, pastes, or gels,” every example composition disclosed in Serup  is aqueous, containing either purified or hot water. Every example also contains almond oil, propylene glycol, or alcohol. Thus, Serup does not recognize the stability problems associated with using water, almond oil, or propylene glycol in the combination formulations. Nor does Serup disclose the use of POP-15-SE or any other solvent that could solve the storage stability concerns.

The Board decision under review by the CAFC relied on Turi as the primary reference because Turi disclosed a category B corticosteroid and a category C solvent. The Board then used Serup or Dikstein with Turi to reject various dependent claims concerning different vitamin D analogs.

The Board followed the Examiner’s reasoning for combining Turi with Serup: “…the reason for combining them was “for the [Turi]  solvent’s advantages and ‘to obtain a more effective preparation without the potential of causing skin atrophy.’” The Board felt that “…both Serup and Turi describe compositions with corticosteroids,  an artisan would have found the two references reasonably pertinent for the “same type of compositions with the same therapeutic purpose.”” The Board added that  adding vitamin D to Turi “would have been obvious to address the well-known side effects of topical steroid treatment.” In addition, the Board held that since Serup discloses selecting  ingredients  that are “compatible” and “not deleterious,” an artisan would have been familiar with selecting components  by routinely “picking and choosing” from a list to achieve a compatible and non-deleterious preparation.

As regards combination of Turi with Dikstein, the Board found that Dikstein “teaches the benefit of combining a vitamin D analog with a corticosteroid to achieve more complete skin healing,” which was a reason to add a vitamin D analog to Turi’s corticosteroid treatment. The Board indicated that the analysis for Serup also applied to Dikstein.

The Board admitted that Leo had submitted “extensive experimental evidence” that water, alcohol, and propylene glycol cause unacceptable degradation of vitamin D and steroid compositions. However, the Board felt that Turi provided explicit guidance to exclude these ingredients.  Specifically, the Board found that Turi excluded water, alcohol, and propylene glycol;  taught that propylene glycol is “irritating to the skin” and “a nonlubricant;” and taught that POP-15-SE solved the problems associated with propylene glycol.

The Board concluded that Leo’s objective indicia of non-obviousness, did not overcome the prima facie case of obviousness because the “unexpected results” claimed by Leo Pharmaceuticals were not unexpected since Turi “provided explicit reason to use POP-15-SE as a solvent.” so that Leo Pharmaceuticals “did not establish that the improvement observed was unexpected to one of ordinary skill in the art in view of the strong reason to have utilized POP-15-SE.”

The Board cited KSR in support of the premise that “the reason for utilizing the solvent does not have to be the same reason [the solvent] was employed by the inventors.”

Those readers that work in  US prosecution probably don’t see much wrong with the Board’s reasoning.

The CAFC did.

The CAFC indicated that the ’013 patent is not simply a combination of elements found in the prior art. The Court credited the inventors with recognizing and solving a problem with the storage stability of certain formulations.  According to the Court, this problem  was both unrecognized and unsolved by the prior art for over a decade.

The Court reminds us that an invention can often be the recognition of a problem itself.  [Cardiac Pacemakers, Inc. v. St. Jude Med., Inc., 381 F.3d 1371, 1377 (Fed. Cir. 2004)]

The Court found it relevant that during reexamination, Leo Pharmaceuticals presented medical research articles published as early as 1995 discouraging the combination of a vitamin D analog with a corticosteroid because of the stability problems of vitamin D analogs at lower pHs. The prior art as a whole seemed to suggest that it was “only natural” for clinicians to attempt to try combinations of vitamin D with other ingredients, but warned that vitamin D should not be combined with other drugs requiring  a low pH (e.g., corticosteroids).  The prior art recognized possible advantages from combining a vitamin D treatment with topical corticosteroids, but nevertheless recommended a two-drug regimen where patients applied the drugs at different times of day or on alternating days.

              

The Court noted that although Dikstein and Serup attempt the combination of a vitamin D analog with a corticosteroid, neither  discloses or addresses the stability problems of combining vitamin D analogs and corticosteroids into one pharmaceutical formulation. 

Leo Pharmaceuticals conducted experiments and submitted evidence to show that  the prior art does  not teach any composition that exhibits storage stable properties.  Every example disclosed in Dikstein contains either almond oil or propylene glycol.  Similarly, the examples disclosed in Serup contain not only water, but also almond oil, alcohol, or propylene glycol.

Leo Pharmaceuticals presented experimental evidence to the Board that each of these ingredients harmed  the storage stability of the vitamin D analog and cortico-steroid combination.

The Court suggests that since neither Dikstein nor Serup recognized or disclosed the stability problem, there was no reason for one of ordinary skill in the art to attempt to improve upon either Dikstein or Serup using Turi.

Now we get to the time factor.

The Court reasons that the ordinary artisan would first have needed to recognize the problem, i.e., that the formulations disclosed in Dikstein and Serup were not storage stable which requires several months running storage stability tests. Only after recognizing the existence of the problem would an artisan then turn to the prior art and attempt to develop a new formulation for storage stability.

And here is the antidote to KSR:

“If these discoveries and advances were routine and relatively easy, the record would undoubtedly have shown that some ordinary artisan would have achieved this invention within months of Dikstein or Serup. Instead this invention does not appear for more than a decade.”

It gets better. According to the CAFC passage of time can be an indication of hindsight (emphases added) :

“…the Board found motivation to combine Dikstein or Serup with Turi because one of ordinary skill would have used vitamin D to solve the well-known side effects of steroid treatment.  However, combining Turi and vitamin D to address the side effects of a steroid treatment is only straightforward in hindsight.  Turi was publicly available in the prior art for twenty-two yearsbefore the ’013 patent was filed, yet there is no evidence that anyone sought to improve Turi  with vitamin D. According to the record, even when Serup published the well-known side effects of steroid-induced atrophy in 1994, no one—including Serup—sought to improve Turi by adding vitamin D to Turi’s corticosteroid composition. Serup even targeted the precise side effects that the Board believed would have motivated the addition of a vitamin D analog to Turi’s corticosteroid composition, yet Serup did not seek to improve Turi by adding vitamin D."

The CAFC also finds fault with the Board’s suggestion  that picking specific combinations from among many possibilities was obvious to try in the context of time (emphases added):

Here, the “background of useful knowledge”—including the prior art relied on by the Board—was published decades before the ’013 patent: Turi issued in 1978, Dikstein issued in 1986, and Serup was published in 1994. The elapsed time between the prior art and the ’013 patent’s filing date evinces that the ’013 patent’s claimed invention was not obvious to try. Indeed this considerable time lapse suggests instead that the Board only traverses the obstacles to this inventive enterprise with a resort to hindsight. It took over a decade—after Dikstein’s disclosure of the benefits of combining vitamin D and corticosteroid treatments into one formulation—for Dikstein’s formulations to be tested for storage stability. And, until the advancement made by the inventors of the ’013 patent, no one had proposed a new formulation that would be storage stable.  The  problem was not known, the possible approaches to solving the problem were not known or finite, and the solution was not predictable.  Therefore, the claimed invention would not have been obvious to try to one of ordinary skill in the art.

Even I will admit, this is an unusual case in terms of both the amount of time between the priority date and the publication dates on the references and in terms of the amount of evidence the patentee presented to demonstrate that what was in some of the references demonstrated an ignorance of the problem being solved. Nonetheless, this case suggests an important strategy for overcoming obviousness rejections based upon old publications.  Those of you that are considering using it should read, and re-read, the entire decision. This strategy will work best when the claimed invention solves a problem that was not previously recognized.

Thanks to the enlightened panel at the CAFC for shedding new light on the meaning of the phrase “rational underpinnings”.  

Cooked in their own juice

The Court of Appeals of the Federal Circuit (CAFC) decided last week that a manufacturer’s request from a sub-contractor to produce a product creates an “offer for sale” which creates a bar to novelty. The case is Hamilton Beach Brands v Sunbeam Products and the decision is available here.

The case revolves around slow cookers that employ clips to hold the lid closed so that food will not leak out during transport. The sole issue considered by the court was whether there was a bar to patentability under 35 U.S.C § 102 due to prior sale of the product.

The case was decided under the old § 102(b):

“A person shall be entitled to a patent unless…the invention was …in public use or on sale in this country, more than one year prior to the date of the application for patent in the United States…”

It seems likely that facts of the case would have given the same outcome under the new § 102(a) (1):

“A person shall be entitled to a patent unless…the claimed invention was … in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention…”

The facts of the case are as follows:

Hamilton Beach’s earliest filing date was March 1, 2006. On February 8, 2005, Hamilton Beach issued a purchase order to its supplier for manufacture of its Stay or Go® slow cookers.  On February 25, 2005, the supplier confirmed that it had received the purchase order and noted that it would begin production of the slow cookers after receiving Hamilton Beach’s release.

The CAFC held that the February 25, 2005 confirmation from the supplier was an “offer for sale” made more than 1 year before the priority date. They also held that the offer was “in this country” because although the supplier was outside the US, the offer was made to Hamilton Beach in the US.

The Court noted that:

“The on-sale bar applies when two conditions are satisfied before the critical date: (1) the claimed invention must be the subject of a commercial offer for sale; and (2) the invention must be ready for patenting.  Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 67 (1998).  An actual sale is not required for the activity to bean invalidating commercial offer for sale.”

This means that Hamilton Beach’s own actions caused another party to engage in activity which made it impossible to obtain a valid patent. In order to avoid this outcome, Hamilton Beach would have had to file a patent application within one year of issuing a purchase order to its supplier, or at least within one year of the date the supplier responded to that purchase order affirmatively.

While the case does not represent a departure from previous decisions, it is interesting for two reasons:

The first reason is that under the new § 102(a)(1) which came into effect in March 2013, there does not appear to be a 1 year grace period for sales activity. This means that under the new law a manufacturer should file a patent application before issuing a purchase order to its supplier, or at least before the supplier responds to that purchase order affirmatively.

The second reason is that the case may be relevant to other business scenarios. Many entrepreneurs employ external engineers or development consultants prior to actual manufacture of their product. Assuming that this employment of external people occurs before filing a patent application a defendant in future infringement litigation will have nothing to lose by saying that the product was “ready for patenting” at the time of the employment, and that the work product returned by the external engineers or development consultants constituted a “sale” or “offer for sale” in the sense of § 102.

What can one do to prepare for such an eventuality?

One thing is to call the order for work something other than a “purchase order”.  The word “experiment” can be helpful. Experimental use enjoys a special status under § 102:

“A use or sale is experimental for purposes of section 102(b) if it represents a bona fide effort to perfect the invention or to ascertain whether it will answer its intended purpose.…If any commercial exploitation does occur, it must be merely incidental to the primary purpose of the experimentation to perfect the invention.” LaBounty Mfg. v. United States Int’l Trade Comm’n, 958 F.2d 1066, 1071, 22 USPQ2d 1025, 1028 (Fed. Cir. 1992) (quoting Pennwalt Corp. v. Akzona Inc., 740 F.2d 1573, 1581, 222 USPQ 833, 838 (Fed. Cir. 1984)). “The experimental use exception…does not include market testing where the inventor is attempting to gauge consumer demand for his claimed invention. The purpose of such activities is commercial exploitation and not experimentation.” In re Smith, 714 F.2d 1127, 1134, 218 USPQ 976, 983 (Fed. Cir. 1983)." [MPEP § 2133.03(e)]

Specifying that work done by external engineers or development consultants is in the nature of “experimental testing” already at the time contractual arrangements are being made has the potential to save a lot of headaches later on.  

Myriad Complications update

Yesterday we  reported that Myriad Genetics had filed a suit alleging patent infringement against Ambry Genteics. Myriad has followed up with an additional suit against Gene by Gene Ltd. in the District of Utah, Central Division.

Since our angle in yesterday's posting was price comparison between Myriad's "Brand Name" BRCA1/2 testing and "Generic" competitors, we wondered  how much Gene by Gene Ltd. charges for their test.  According to an online press release, Gene by Gene will be charging $995 for BRCA1/BRCA2 testing in the US.

Myriad complications

On July 9, 2013 Myriad Genetics filed suit against Ambry Genetics in the District of Utah, Central Division for infringement of numerous patent claims in several patents which Myriad either owns or holds the license for. A copy of the complaint can be seen here   A detailed analysis of the claims asserted has been posted by Patent Docs as Myriad Genetics Files Suit Against AmbryGenetics for Genetic Diagnostic Testing of BRCA Genes .

For those of you that are not familiar with the story, Myriad Genetics has patent rights for BRCA1 and BRCA2 screening. A consortium led by the ACLU and AMA spent several years in court trying to get some of the Myriad patent claims invalidated as being directed towards non-patentable subject matter. Ambry is a "generic" competitor offering similar screening following the outcome of the earlier lawsuit.

The current complaint is in response to an announcement by Ambry that it would begin to offer BRCA testing .

One interesting thing is that Ambry offers three different types of BRCA tests, priced at $3300; $2200 and $500. Ambry also indicates that it will provide BRCA1 and BRCA2 gene sequencing and deletion/duplication results at no extra charge as part of its existing “BREAST NEXT” ($4,120); “OVANEXT” ($5,310) and “CANCERNEXT” ($5,830) NGS panels.  Those of you that have been following the Myriad saga from the district court in New York, to the Court of Appeals of the Federal Circuit (CAFC) and then to the Supreme Court (SCOTUS) are aware that the plaintiffs (including the ACLU and the AMA) were vociferous in their opinion that the patents held by Myriad were keeping the cost of BRCA1/2 testing high, to the detriment of women that wanted to know what their risk of developing breast cancer/ovarian cancer is. 

For the sake of comparison, testing by Myriad Genetics is priced at about $3000 (data from Maricopa IntegratedHealth Services).

To the best of my knowledge, neither the ACLU nor the AMA has criticized Ambry’s price schedule. 

Myriad genetics offers a financial  assistance program for uninsured patients, and a 25 month payment plan for insured patients. Ambry genetics also offers a financial assistance program. Comparison of the relative merits of the two financial assistance programs is beyond the scope of this blog.

Looking at the list prices, it is not at all clear if testing by Ambry is significantly cheaper than testing by Myriad. Even with a Ph.D. in molecular biology I’m not sure what are the differences between the $3300; $2200 and $500 tests offered by Ambry. It seems likely that the typical patient concerned about her future risk of breast/ovarian cancer has less than a Ph.D. in molecular biology. While we would all like to believe that her primary care physician can provide meaningful guidance on the differences between the $3300; $2200 and $500 tests, that is not always the case.

Hypothetically, a woman that received “bad news” from the $500 Ambry test could easily consider ponying up another  $3300 or $2200 before undergoing the double mastectomy/ovarectomy she was presumably contemplating if she took the test. This would bring the total cost into the same price range as the Myriad test or higher. 

Conversely, a woman that received “good news” from the $500 Ambry test might still be uncertain as to the reliability of the “cheap test” and  lay out  another  $3300 or $2200 to be certain she doesn’t need a double mastectomy/ovarectomy.  After all, the ACLU and AMA also stressed the importance of a woman’s right to a second opinion. Again, this would bring the total cost into the same price range as the Myriad test or higher. 

So, what did the much touted legal battle concerning the BRCA portfolio belonging to Myriad genetics actually accomplish?

Well, some patent claims were invalidated by the CAFC. Additional patent claims were invalidated by SCOTUS. 

Was this a victory for the ACLU, the AMA and the various patients and doctors that joined the suit? 

Perhaps not. 

The Supreme court decision clearly indicates :

“[a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications.”

SCOTUS did what it routinely does. It issued a decision, accompanied by a clear statement of what that decision does not do. 

One of the things the SCOTUS decision does not do is prevent Myriad from enforcing its rights based upon any claims not invalidated by the CAFC or SCOTUS. While there is a theoretical possibility that the District of Utah, Central Division will find that Myriad is estopped by the previous lawsuit, that seems unlikely.  One reason is that Myriad is physically located in Utah and therefore enjoys a “home court” advantage.  Another reason is that Ambry was not a party to the previous lawsuit; presumably because they were not offering testing services which could be perceived by Myriad as infringing their patent claims until after the previous suit had run its (incredibly long) course. Another reason is that the claims at issue in the case against Ambry were not at issue in the previous case because there was no allegation of infringement in that case.

The previous lawsuit seems to have helped Myriad retain exclusive control of the market for several years. The current complaint against Ambry seems likely to help them retain that exclusive control for several more years. 

Kudos to those that conceived and executed the Myriad BRCA patent portfolio. One of my mentors said “A good portfolio is one that takes so much time and money to analyze that nobody will do the analysis.”  That seems to be the case here. The analysis will occur during litigation and/or licensing negotiations.

Since the initial suit against Ambry is to be heard in a friendly jurisdiction, by a jury, and since the issue of section 101 patent eligibility has already been addressed by the courts, I predict that Ambry will need to do what all accused infringers hate to do: focus on whether infringement is actually occurring at trial.

Whether Myriad will visit the CAFC and/or SCOTUS again is anybody’s guess.