The salt form jinx:Delhi HC denies interim relief to Merck


The Delhi HC (Justice Rajiv Sahai Endlaw) refused to grant interim relief to Merck (plaintiff) seeking to restrain Glenmark (defendant) from launching its products Zita and Zita met. We had blogged about it here and here. The High court however kept the main petition of the US firm pending for evidence filing and other legal proceedings on July 16.The order passed on Friday can be accessed here.Following is summary of arguments presented by either side. (Long post warning!) 

Image from here

On the issue of separate patents for Sitagliptin and salt form of Sitagliptin: 


Glenmark’s arguments:

Senior counsel for the defendant alleged that plaintiffs are guilty of suppression and had failed to disclose that the patent application (probably referring to the 5948/DELNP/2005) for the product for which injunction was sought was not only declined and also abandoned. 

Glenmark’s counsel elaborated that its product comprises of three parts “S”, “PD” and “DC” (possibly referring to Sitagliptin, dihydrogenphosphate salt and crystalline form), and that Merck has separate patents for each of these parts in USA. Glenmark’s counsel further detailed that Merck holds the patent in India only for the first part and separate patents for the other two parts i.e. phosphate salt and crystalline form were denied and affirmatively abandoned. 
Glenmark’s counsel also argued that Merck in its patent application (5948/DELNP/2005) had described that the combination of S and PD i.e. (Sitagliptin and phosphate salt) as a new discovery not covered by existing Sitagliptin patent. In light of this Merck cannot allege that defendants combination of “Sitagliptin and phosphate salt” infringes Merck’s patent. Glenmark also stated that “plaintiffs patent is for Sitagliptin Hydrochloride only and not for Sitagliptin Phosphate.” Placing reliance on Paras 139 and 156 of the Supreme Court Novartis judgement, it was contended that “coverage in a patent cannot be permitted to go much beyond the disclosure made by the patentee” 
It was also argued that if Sitagliptin phosphate and Sitagliptin weren’t distinct products, then Merck wouldn’t have applied for separate patents for each of those in US and India. 
Merck’s arguments:
It was argued that Sitagliptin was the invention and Sitagliptin phosphate was merely a derivative and therefore wasn’t eligible for patent protection under Section 3(d).The separate patent application for Sitagliptin phosphate filed by Merck was due to some misconception, which is why they affirmatively abandoned the same. It was also stated that, separate patent for Sitagliptin phosphate was applied for since the US has no Section 3(d) equivalent patent law. 
On the issue of Infringement 

Glenmark’s arguments:
Analogy was drawn to the Roche vs. Cipla (2012) judgement in which the plaintiff sought to injunct the product version for which the patent application was rejected. On the basis of Roche vs. Cipla judgement it was argued that when the role of the variant (in this particular case Sitagliptin phosphate) outweighs the patented claim (Sitagliptin only), there can be no infringement. Shamnad’s posts on Roche vs. Cipla judgement are available here and here
Merck’s arguments:
Merck’s counsel argued that the package insert information reveals that the pharmaceutical composition of plaintiff’s product is similar to composition of Glenmark’s product Zita and hence the infringement is obvious. Merck’s counsels also emphasized that “there is no price difference in the product of the plaintiffs and defendant” to allay the influence of Novartis supreme court decision
On the presence of other infringers in the market 

Glenmark’s arguments:
Glenmark’s counsel also stated that since there are other (about 8-10) infringers in the market selling the same product for which injunction is sought, the ingredients of irreparable injury and balance of convenience are not in favour of the plaintiffs. 
It was also argued that grant of patent does not automatically create any presumptive validity (section 10 and 13(4) of Indian patent act) and since there are others in the market using the same formulation for which injunction was sought “there was no new invention.” 
Merck’s arguments:
The response of the plaintiff to the plea of the defendant that at least 9 to 10 other persons were also marketing Sitagliptin Phosphate was that instructions on that aspect will have to be taken once duly supported documents were handed over. 

DECISION :Observations of the Court 

Whether Glenmark’s product using a combination of Sitagliptin with its phosphate salt will have a material effect upon the working of Sitagliptin per se? 
The learned judge agreed that Merck’s granted patent includes within its ambit “pharmaceutically acceptable salt of Sitagliptin” which may of course include Sitagliptin phosphate (Glenmark’s product). 
The judge also reasoned that plaintiff should have shown that, defendant’s product inspite of combining phosphate salt with plaintiff’s patented Sitagliptin remained equivalent to Sitagliptin and that the role of phosphate was inconsequential in treatment of the disease. 
The judge also noted that Merck has had made a separate patent application for Phosphate salt form of Sitagliptin, considering it to be a new invention worthy of a separate patent. Plaintiff (Merck) has not satisfactorily pleaded the circumstances for obtaining a separate patent application. 
Justice Endlaw also elaborated that the defendant had also pointed out that there were at least 9-10 infringers marketing Sitagliptin phosphate. “Though, ordinarily infringement by others does not constitute a ground for denial of the relief of injunction against an infringer but it can be a consideration in the grant of interim injunction.” 
“I therefore do not find the plaintiffs to have made out a case for grant of interim relief” 
Conclusion: 
I may be oversimplifying things here, but claim 15 of Merck’s granted patent on Sitagliptin IN209816 clearly states “The compound as claimed in claim 1 (referring to markush structure of gliptins) selected from the group consisting of or a pharmaceutically acceptable salt thereof.” 
Also the specification of the patent defines salt forms as “When the compound of the present invention is basic, salts may be prepared from pharmaceutical acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsuifonic, citric, clhanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isclhionic, lactic, maleic, malic, mandclic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.” 
So,wouldn’t it be reasonable to conclude that anyone who markets the disclosed salt forms of Sitagliptin infringes the patent claims? So how does it matter that Merck tried and failed to patent the salt form separately in another patent in India. Hope our readers can help me out here!

Madhulika Vishwanathan

Madhulika Vishwanathan

Madhulika is a registered Indian patent agent and has completed her Master’s in Pharmacology from the Institute of Chemical Technology (ICT), Mumbai. Her interests include issues involving pharmaceutical and biotechnology patent law, regulatory aspects like Hatch Waxman litigation and antitrust law.She is currently working at law firm based out of Memphis, TN.

12 comments.

  1. AvatarAnonymous

    It would be reasonable. The fact that Merck filed a patent application on the phosphate salt has nothing to do with the scope of the compound patent claims. Its patentability in a separate patent application is a completely separate question. But the erlotinib case shows that strange decisions are not altogether unusual in our courts. Judge Endlaw himself delivered a very strange decision in the entecavir case involving DCGI, creating patent linkage out of thin air and thus legislating from the bench. Mercifully, it was quickly overturned by Justice Ravindra Bhatt. So, who knows what’s in store in this case?

    Reply
  2. AvatarAnonymous

    I am not from pharma background but on the face of it if sitagliptin was covered by the claim, then any salt form of it would also be covered. I fail to understand how it will be non infringing? Did Merck during prosecution gave up any specific salt form of sitagliptin?

    I feel the court should have looked into more details before passing adverse order against Merck.

    Reply
  3. AvatarAnonymous

    I posted a query on the discussion in Roche Vs Cipla on this blog…

    I understand the above as under:
    Merk has a patent on sitagliptin compound or pharmaceutically acceptable salts thereof

    (Wherein the phosphoric acid is mentioned as one of the salt forming acid)

    Therefore any form of Sitagliptin Phosphoric acid salt according to me will be infrnging the claim on the compound and the salt form .

    Here glenmark is using Merk’s own specification for a crystalline salt form to show that the said form is distinctively different from the compound even according to the plaintiff.

    Earlier it was seen that roche could not lead evidence to show that the difference between the two forms is not significant lest it shoud affect the patentability of their subsequent form patent in the US.

    However, I feel instead of showing that the difference in the forms is insignificant, merk should lead evidence to show that in order to to produce the crystalline salt form, their patented compound (sitagliptin or sitagliptin phosphate) is used…

    Then whether they filed patent application for the other form or succeeded to obtain a patent in US and failed in India becomes irrelevant to decide the infringement of their first valid patent.

    Please Correct if any one feels that my understanding has a falw.

    DAB

    Reply
  4. AvatarAnonymous

    @Madhulika – just two comments:

    “Merck’s arguments:
    It was argued that Sitagliptin was the invention and Sitagliptin phosphate was merely a derivative and therefore wasn’t eligible for patent protection under Section 3(d).The separate patent application for Sitagliptin phosphate filed by Merck was due to some misconception, which is why they affirmatively abandoned the same. It was also stated that, separate patent for Sitagliptin phosphate was applied for since the US has no Section 3(d) equivalent patent law.”

    This submission of Merck appears to be contrary to what is stated on page 2 of their phosphate salt application – portion reproduced below for reference:
    “However, there is no specific disclosure in the above reference of the newly discovered
    monobasic dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-
    a]pyrazin-7(8//)-yl]-l-(2,4,5-trifIuorophenyl)butan-2-amine of structural formula I below.”

    Second, identity in package inserts cannot generally be equated with infringement, unless of course patentee identifies the patent on the packaging and is also able to demonstrate this through evidence.

    The file wrapper in respect of the Sitagliptin patent available on IPAIRS is woefully inadequate. Anyway, while the description does refer to a phosphoric acid salt as part of a general list of pharmaceutically active salts, the examples do not actually appear to provide any support for the specific salt in question. Given this, and the statement on page 2 of the phosphate salt application, the order appears well reasoned.

    Finally, do we hear Glenmark singing the old George Harrison number “Here comes the Sun”!!!!

    Regards,

    Nataraj

    Reply
  5. AvatarAnonymous

    Merck Patent IN209816 has claimed Sitagliptin base structure under Markush structure (generalized structure for a set of chemical compound). Making any derivative or salt containing this base structure would infringe the said patent. Moreover, Merck has broadly claimed pharmaceutically accepted salts of Sitagliptin which covers phosphate salts. Hence, any phosphate salt of sitagliptin would fall within the scope of IN’816.

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  6. AvatarAnonymous

    DAB writing as DAB – you are pretty close to hitting the nail on the head. I have been wondering for the past few days as to when Merck will “make” and “use” Section 48 – to coin a very bad pun.

    There is actually no reason to go down the Section 3(d) route as an inverse justification for infringement.

    The fact situation as I see it with my limited understanding is this:
    (a) Merck has a patent for Sitagliptin base molecule;
    (b) Glenmark makes and sells Sitagliptin phosphate which is actually covered by a subsequent abandoned/cancelled application of Merck;
    (c) The only route to make Sitagliptin phosphate that is commercially sold is using Sitagliptin that is patented;
    (d) Section 48 provides protection against any commercial making/using of a patented product;
    (e) Ergo, making and selling Sitaglipin phosphate would amount to an infringing activity, since to do so, it will first be necessary to make and use Sitagliptin which is a patented product.

    If the injunction prayer requests that “manufacture” and “use” of Sitagliptin be stopped, you have effectively achieved what you want.

    For [email protected] – the fact that the earlier patent states that phosphate salt is one salt is not sufficient to provide protection for a specific salt form, particularly when the applicant in question has specifically averred in the second application that it is not covered. Prosecution history estoppel and equitable conduct militate against ignoring a specific averment made to a statutory authority. Prosecution history estoppel is not necessarily limited to the specific patent in question, but extends to other prosecution histories of the same applicant in the same technology segment.

    Regards,

    Occasionally Annoyingmouse

    Reply
  7. AvatarMadhulika Vishwanathan

    Thanks much for your for your insightful comments Natraj. I have the following points to make.

    1. How is Merck’s submission contrary?
    Yes there is no specific disclosure of the salt , it was a generic disclosure

    2.Generic drugs are by defn bioequivalent and thereby chemically equivalent , there is lots of evidence on that count.

    3.Also the issue of separate patent applications for Sitagliptin and Sitagliptin phosphate is independent of the issue of infringement…

    How can you make the salt form of any product without making the actual product itself ??

    If you use “sitagliptin” to make “sitagliptin phosphate” its infringement (sec 48)

    Best,
    Madhulika

    Reply
  8. AvatarAnonymous

    Madhulika,

    My comment at 9.30 covers it.

    The way I see it, there were two routes to establish infringement – (a) make use of the “making, using” in Section 48 and rely solely on the 209816 patent. Disclose the subsequent filed application and its status but make it clear that it is not being relied on per se. Submit that infringement is because Sitagliptin is being “made” and “used” when making a formulation containing the specific phosphate salt.
    (b) rely on the Sec. 3(d) inverse route.

    I have not seen the pleadings. However, I personally believe that the first route would have been an easier one to establish.

    My point on the contradiction is based on patentee’s own statement in a subsequent patent application. The complaint is with respect to a specific salt form. The subsequent application states that it is not covered in the original (which has been granted), I would believe you are looking at a “hoist” and “petard” situation.

    This would leave it open to any prospective defendant to argue that the phosphate salt reference in the original granted patent was purely speculative, based on patentee’s own admissions in subsequent applications, and an injunction is effectively still an equitable remedy.

    Regards,

    Nataraj

    Reply
  9. AvatarAnonymous

    Dear Nataraj/Madhulika,

    I wanted to write this long time back.

    I am not sure as to how, inverse section 3(d) can help merk prove the case of infrigment of thier valid patent without using the “make-use” torpedo.

    At the max 3(d) can provide a justification to the abandonment of thier patent application.

    I feel that merk’s stance can overcome the objection (weak though) of being contrary by establishing that the compound patent (sitagliptin) that discloses the salts (such as sitagliptine pO4) in a generic manner can not automatically make all the novel salt forms that can be derived from sitagliptin noninfringing!!
    for example consider the following:

    If I have a patent on a drug (A) which is valid and which mentions that A can be used in combination with so-many other drugs. Then, I file patent application for a combination of two drugs (A+B) which is not disclosed specifically, I may abandonn my second application but the third party planning to market A+B is liable to infringment of my patent on A since by claiming invention in A+B I did not give up my invention in A!!!

    DAB

    Reply
  10. AvatarAnonymous

    It seems like Glenmark is trying to build double story building without touching the ground floor which is protected by Merck.

    Hence, if decision goes in favor to Glenmark, it would be a green flag to other generic and definitely change our mindset towards determining infringement specially in India as well.

    Avishkar IP

    Reply

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