Bayer – Part II – Are Patents for Bio-Similars Elligible for Patent Term Extensions???

This is the second part of a ruling concerning Patent Term Extensions (PTEs) for Kovaltry. The first part related to when the ninety day period from registration commences and is discussed here.

This second part of the ruling is a precedential decision that rules whether a patent for a bio-pharmaceutical material such as a protein can be can be considered as being a basic patent if there is a previously registered bio-similar molecule; it being appreciated that the amino acid sequence may be the same, but the spatial structure, activity and efficacy may still be different. In view of its legal and financial significance, the decision is fully translated below. We apologize for any incorrect technology. 

After the request for a patent term extension for Kovaltry was received from Bayer, the Patent Office issued an Office Action as follows:

Paragraph 6 of the Affidavit appended to the letter of 22 August 2017 notes that there is no other formulation that includes Recombination Human Coagulation Factor VIII, fabricated by the defined cell culture and the defined conditions under which KOVATLRY is manufactured. It is possible that the Blood Coagulation factor claimed in the Application is different from the Blood Coagulation Factors that have been registered, but the Active Ingredient of the Recombination Human Coagulation Factor VIII formulation is registered in the registry of pharmaceutical formulations in various formulations mentioned hereinabove.

The other medical formulations mentioned as including Factor VIII were Novoeight, Octanate 1000, Koate and Kogenate.

Kovaltry

On 11 December 2017, the Applicant responded to the Office Action and claimed that the active ingredient, the Recombinant Human Coagulation Factor VIII, is a new material derived from a new genetic engineering process that is protected in the present application, and that Kovaltry is the first formulation that allows its medical usage in Israel, as required for a patent term extension in Section 64D(3) of the Law.

The Applicant explained that Factor VIII is intended for treating Hemophilia A which is characterized by a problem with blood clotting due to a fault in or a lack of Factor VIII. In the new process covered by the Application, the heat shock protein 70 (HSP70) is introduced into the gene of the host cell and additional actions are taken to produce the active ingredient, which creates a new protein Factor VIII, which has a different structure from other proteins that relate to a lack of endogens in the Factor VIII coagulant. The structure of the protein, as applied for in the Application is as follows:

Bayer

The Applicant further explained that the folding structure of the protein is different due to the manufacturing route, and it attracts a lot of sugar groups (glycans), which allow the protein to automatically fold and provides a pharmokinetic advantage to the protein when compared to other formulations. In this regard, the Applicant notes that most properties, such as the glycan group appended, which have been glycosylated, are relevant to the half-life of the protein in the blood.

The Applicant claims that the registration file of the Kovaltry formulation indicates that the Ministry of Health considered the formulation to have a new active ingredient, and so it had to undergo the specific regulatory requirements of the Ministry of Health. The Applicant relies on the Procedure of the Ministry of Health for registering products of this type; Changes and Innovation in Medical Formulations from 1 February 2015, which differentiates between six different categories for registration.

According to the Applicant, when the Israel Ministry of Health relates to the Recombination Human Coagulation Factor VIII as being a new active ingredient as far as registration in the drug register is concerned, one has to apply a similar rationale when considering the drug for a patent term extension in order to fulfill the purpose of the legislation which is the underlining logic of the patent term extension, which is to compensate the patentee for the period when he cannot market the formulation containing the patented product due to regulatory requirements. The Applicant argues that one should differentiate between medical formulations that have active chemical ingredients that are small molecules, and biological formulations that are differentiated by proteins manufactured in different ways. They argue that the different proteins are typically different from each other in both their structure and their physical properties.

From the claims it transpires that the difference results from the way that the protein is manufactured. The applicant explained and supported their explanation with various appendices, the manufacture of a biological pharmaceutical formulation that includes proteins is very difficult due to the size of the protein, the way it folds, the general structure, changes in translating the chain of amino acids to create the protein, the cell culture used to manufacture the proteins, and so on. All changes lead to changes in the protein itself, in its. glycosylation and medical effect.

Due to these differences, the Applicant alleges that Health Ministries around the world have created different regulatory procedures for biological pharmaceutical formulations. They claim that even though there may be several medical formulations for addressing a lack of a particular enogen, such as Factor VIII, due to the issues raised above, they will be different from each other in practice. Furthermore, their active elements which cause blood clotting will be different and have different international classification.

In their response, the Applicant further explained that there are other formulations that treat Hemophilia A, which are fabricated in different ways such as by separating active ingredients from human plasma, formulations obtained by genetic engineering of part or a full gene, formulations that include healed proteins and formulations that include Factor VIII with additional proteins.  The Applicant claims that these formulations are completely different from Kovaltry, despite their purpose being to overcome the endogenic lack of the blood clotting Factor VIII as described above.

The Applicant focused on the differences between the active ingredients of the medical formulations cited by the Examiner and the active ingredient of Kovaltry. As to Kogenate, the Applicant claimed that its active ingredient was different to Factor VIII, even though the sequence of amino acids was the same, since the proteins of the structure are different at the gene level and the protein level. The Applicant appended journal articles that related to the differences between the formulations as an example of improved pharmakinetics.

In light of the above, the Applicant considers that one cannot apply Section 64D(3) of the Law in the same way for biopharmaceuticals when comparing active ingredients with prior art as is done for chemical pharmaceuticals.

In response to these claims, the Deputy Chief Examiner responded in a letter of 31 December 2017, that obtaining the strict regulatory approval required for pharmaceuticals is no indication that a patent term extension is also appropriate. To support this differentiation, the Deputy Chief Examiner referred to 223/09 H. Lundbeck A/S vs. Unipharm ltd et al (22 May 2009).

The letter also notes that the journal papers appended to the response explain that the process for obtaining Factor VIII in the patent in question creates a new protein with a different structure, with glycosylation and different pharmakinetic properties which affect the half-life of the protein in the blood, but do not influence the formulation, and the protein that is the active ingredient of Kovaltry is Factor VIII which exists in Kogenate and other pharmaceutical preparations.

Furthermore, the Deputy Chief Examiner considered that the improved glycosylation or the addition of the HPS70 may affect the folding and could be a new process, but the registration of a medical preparation is given for a formulation and not for the process of manufacture, and differences in the Factor VIII are simply a bi-product of the processing route.

The Deputy Chief Examiner added that though the process of manufacturing the proteins in Kovaltry and Kogenate are different with a difference that expresses itself in yield, better cells and other repeatability differences, the sequence of amino acids is the same, despite the amount of glycans that underwent glycosylation on the proteins So compared to preparations that were registered earlier than Kovaltry, the Deputy Chief Examiner rejected the Applicant’s claims with respect to each of the formulations.

On 7 February 2018, the Applicant submitted a request for a hearing regarding the rejection, and submitted a further statement of claims on 20 February 2018. O 25 February 2018 an ex-partes hearing was held before the Commissioner during which the Applicant reiterated their claims and added the following claims:

Factor VIII is a complex protein and changes in the process result in significant changes to the structure thereof and to the medical affect thereof. Consequently, when comparing twoproteins to ascertain whether or not they are the same material, one has to consider the structure and not merely the sequence of amino acids which is the first stage of characterization, but also the three dimensional form and the intracellular activity.

After the hearing, the Applicant submitted a summary on 1 March 2018 that proposed an appropriate test for considering the novelty of biopharmaceuticals. The proposed test has three levels. Firstly one should consider if the material is a biological medicine. Then one should consider if the protein has a new structure, and finally various tests for determining whether a protein is new or not, such as whether it is a specific protein, whether the regulatory approval was for a new material or for a biosimilar, and the properties and structure of the protein. In conclusion, the Applicant detailed why the present invention should be considered a new material.

The Applicant cited American, British, Norwegian and Dutch case law.

Discussion and Ruling

Section 64D of the Law establishes the conditions for granting a Patent Term Extension (PTE). The condition given in Section 64D(3) of the Law is that the active ingredient given in the patent for which the extension is requested, has not previously been registered in the Register of Medical Formulations. This is the wording of the Law:

(3) The registration mentioned in Paragraph (2) is the first registration that allows use of the active ingredient for medical use in Israel;

compensation 2

The purpose of the legal arrangement relating to the period protected by the patent is to compensate the patentee for the period that he cannot utilize the patented invention due to regulatory requirements. Nevertheless, the legislator did not rule that in all cases the patentee would be compensated, but only in such cases that the formulation was not previously registered. As will be discussed ad nauseam at length below, the rationale behind this order is to compensate applicants undergoing complete regulatory approval, due to the time required for this.

The question when to see the registration in the register as the first registration that prevents a subsequent application from benefitting from a patent term extension, has been dealt with extensively in Patent Office rulings, and in District and High Court decisions.

The question when to see the registration in the register as the first registration that prevents a subsequent application from benefitting from a patent term extension, has been dealt with extensively in Patent Office rulings, and in District and High Court decisions.

Chemical-structure-of-citalopram-enantiomers

Thus in re Lundbeck, the question of whether Escitalopram (the active ingredient of Cipralex) was discussed, where Escitalopram is the S enantiomer  that exists in the racemic mixture of Citlopharm which, was previously registered in the register of the Ministry of Health as being the active ingredient of Cipramil. The request for a Patent Term Extension was rejected by then Commissioner Dr Meir Noam, after an Opposition procedure; see Opposition to IL 90465 Unipharm vs. Lundbeck A/S, 3 February 2009.

The District Court ruling in re Lundbeck, that was the result of an appeal of this decision, established principles for considering the identity of active ingredients. In paragraphs 16 and 17 thereof, it was ruled that:

Section b(1) of Chapter 4 of the Law does not give the Commissioner of Patents the discretion to condition the granting of a patent extension ruling or the period thereof on data relating to the amount of effort and the time expended by the patentee to develop the invention or to obtain regulatory approval from the Ministry of Health. The conditions for obtaining a Patent Term Extension are standardized and technical, as is the duration of the extension.

The job of the Commissioner when processing a Request for a Patent Term Extension is limited to determining if the formal conditions given in the Law are fulfilled, without any need or ability to relate to the way the patent invention operates or to the effort expended by the patentee in development or in obtaining regulatory approval. This is the way that the legislators chose to balance the competing interests (of the patentee and of third parties) regarding the issuance of a Patent Term Extension for a pharmaceutical invention.

Section 64D(3) of the Law was interpreted there as:

The technical and formalistic approach are interleaved in the conditions of Section 64D(w) of the Law: The registration referred to in paragraph (2) is the first registration that allows the material to be used in Israel for medical purposes. The Commissioner is not expected to engage in detailed research into the properties and activity of the material protected by the basic patent. All he needs to do is to clarify whether same material is an active ingredient or alternative form of an active ingredient that is allowed more than once for use in Israel in a pharmaceutical formulation.

The District Court added to this, and ruled (Paragraph 17) that definition of the term ‘material’ in the Law teaches that different forms of the same formulation will be considered the same material, even if they are not identical:

The material protected in the basic patent need not include the previous formulation in the original form, but could be a salt or ester thereof and would still be considered as being the same material.

The then Commissioner reached a similar conclusion in re Lundbeck paragraph 49.

The Lundbeck ruling was appealed to the Supreme Court (Appeal 5267/09 H. Lundbeck vs. Unipharm ltd 15 March 2010), but the Supreme Court refrained from defining Section 64D(3):

In light of the result reached, there is no room to argue that the addition of the Israeli Drug Development Lobby Pharma Israel can render further consideration unnecessary, since the ruling of this Court will oblige the District Court and the Patent Office, and become fixed Case Law (compare re Barzani above, page 925, since in this instance we do not need to interpret Section 64D(3) of the Patent Law. Therefore, consideration of the process and its ramifications lead one to the result that there is no place to include Pharma Israel as a respondent in this process.

And then in paragraph 69:

Our eyes see that using the terms like “including’ and ‘possible’ are also mentioned by the Complainant and at the end of the day, the tests suggested by both parties are the same. The Applicant claims that one should look into whether there is an earlier registration that allows usage Escitalopram, whereas the Commissioner considered whether there was an earlier registration that allowed usage of Escitalopram which is simply the S (sinister – left handed)  enantiomer (as acknowledged by the Applicant). The answer, according to the Commissioner of Patents, is the affirmative, since the Escitalopram enantiomer was inherent in the Citopharm racemic mixture of the R and S molecules.

It seems that the Supreme Court only recognized the specific case before it in re Lundbeck, and ruled that registration of a racaemic mixture precludes the subsequent registration of either of its antiomers as being considered the first registration.

The case before us raises a subject that has not previously been discussed. When are two proteins that serve as the active ingredient in pharmaceutical formulations considered so similar that registration of the one in the pharmaceutical register would be considered the first registration of the other protein under Section 64D(3) of the Law?

Particularly, the question is raised whether a technical formalistic test as in the Lundbeck case is appropriate for this instance, when considering the underlying rationale of the legislation.

The Definition of Active Chemical Ingredients

Section 64a of the Israel Patent Law defines the terms ‘material’ and medical formulation’ as follows:

 In this Article –

“medical preparation” – any form of therapeutic drugs that underwent processing, including a preparation for use in veterinary medicine and a preparation of nutritional value intended to be injected intravenously;

 “material” – the active component of a medical preparation or salts, esters, hydrates or crystal forms of that component;

From these definitions it is clear that the materials considered by the legislators were active chemical ingredients.

Recently, the terms “materials” and “formulations” in the pharmacist’s Ordinance were updated, as part of the 2016 amendment of 7 April 2016, such that the definitions were adapted to be appropriate for biological materials in addition to chemical materials:

“material” – a material from any source whatsoever, including human, animal, plant and chemical material;

“formulation”, “medical drug” – any form of the material of combination of materials that includes one of the above, except for blood or blood component that is harvested from a person and is intended to serve its original physiological purpose, and has not undergone substantial processing:

  • It has properties to heal or prevent an illness in persons or animals or to treat such an illness, or is presented as having such properties:
  • It causes, or is prescribed to man or animal to cause, to restore, to exchange, to mend or to change a physiological activity in the body by a pharmacological, immunological or metabolic action;
  • It is given to man or beast for medical diagnosis or could be given for such a purpose;

In this context, it is noted that the term “medical formulation” was removed from the Ordinance in 2015.

The Unique Characteristics of Protein Based Drugs

Biological drugs are based on proteins with significantly different characteristics than drugs based on chemical material. Particularly, the molecules are very much larger.

amino acid

In addition, proteins have a three-dimensional structure that has a decisive influence on the activity of the protein as an active medical ingredient.  Little differences in the amino acids from which the protein is composed can change the three-dimensional structure of the protein and its activity which can vary with the position of the changes in the amino acids and the amino acids of the protein that have been switched.

The manufacturing process of chemical materials consists of synthesizing the desired molecule from atoms and basic material. The same molecule may be synthesized by different chemical processes, and there are precise analytic techniques for determining the molecular structure and the identity of each molecule.

non uniform

In contrast, biological materials are generally manufactured in host cells (bacteria or yeast) by recombinant processing. The conditions under which the protein is manufactured is likely to have a significant impact on the end result. So changes of temperature, acidity levels, saltiness, the type of cell used for manufacturing the drug can all affect the final product, so the same process may lead to non-uniform proteins being manufactured, and the changes are generally more significant when different processes are used.

generic

In light of the above, drugs that include chemical active ingredients exist in generic versions. A generic version is authorized when the active ingredient is equivalent to that of the source in strength and dosage, and it is proven that it has the same efficacy and blood absorption rate as the original drug.  There is no need for full regulatory processes to register the drug in the pharmaceutical register (see the Ministry of Health procedure for applying for registration, changes and renewals for medical formulations to the department for registering formulations, February 2015 (appendix 3). The regulations in the appendix that relate to generic formulations do not apply to biological formulations.

In contradistinction, biological drugs do not have generic equivalents, since one cannot create proteins that are identical to those of the approved drug (in other ways). Even when the sequence of amino acids that defines the basic structure of the protein of the generic product is identical to that of the approved drug, there is no guarantee of similar biological activity, since the three-dimensional structure may be different, the glucolization profile may be different and as a result the effectiveness and safety of the drug may be influenced.

complez

As transpires from the supporting documentation submitted by the Applicant, the manufacturing process for recombinative proteins serving as medical formulations is very complex and different from the manufacture of chemical molecules, and their commercial-scale production is very complex., and the manufacture of one formulation several times may yield different products each time, and a ‘similar’ product may have different immunological effects in different patients. See for example,  Heidi Ledford First biosimilar drug set to enter US market, Nature Vol. 517, 253, 15.1.2015; Martin Kuhlmann, Adrian Covic; The protein science of biosimilars, Nephrology Dialysis Transplantation, Volume 21, Issue suppl_5, 1 October 2006, Pages v4–v8.

In light of the above, the Health Authorities have had to develop general rules to authorize ‘copycat’ or ‘parallel drugs’ to protein drugs. These drugs are referred to as being bio-similar or follow-on-biologics.

biosimilar

The main principle of these general rules is to allow registration of bio-similars after proving that they are not different from the regulated drug regarding which they are considered to be bio-similars with regard to safety, efficacy and quality. Nevertheless, the bio-similar is not allowed as an interchangeable drug for patients who are already being treated by the original formulation.

For example, the procedures that have been determined by the relevant authority for registration of the drugs in Europe, the European Medicines Agency (CHMP/437/04 Rev. 1, see here relates to the data that needs to be produced to show that the new biological formulation is indeed similar to that which is already authorized for marketing.

In Section 3.1 of the procedure, it is specified that existing approach for providing data regarding generic formulations is insufficient for biological formulations, inter alia, because of their complexity:

“The active substance of a biosimilar must be similar, in molecular and biological terms, to the active substance of the reference medicinal product. For example, for an active substance that is a protein, the amino acid sequence is expected to be the same.”

In the same section, it is also specified that:

“Intended changes to improve efficacy (e.g. glycooptimisation) are not compatible with the biosimilarity approach. However, differences that could have an advantage as regards safety (for instance lower levels of impurities or lower immunogenicity) should be addressed, but may not preclude bio-similarity”.

It is further specified that the conditions were established to save the Applicant of the new formulation from conducting unnecessary clinical trials (pages 5 and 6 of the procedure).

Similar rules are found in the procedure for registering pharmaceuticals with the Ministry of Health. The procedure shows that the Ministry of Health differentiates between the different kinds of medical formulations that are submitted for registration. For the current discussion, the following cases are relevant:

  • Formulations that include an active ingredient that is new to Israel are classified in Group 1.
  • Generic formulations are defined as “medical formulations that include a material or materials that are active at a strength and dosage identical to that of a medical formulation registered in the National Drug Register, excluding biological formulations or blood products” – these are classified in group 2.
  • A biological product that is similar (BIO-SIMILAR) – is defined as a biological formulation that is similar to the active ingredient of an original biological formulation that is registered in the National Drug Register. If a request to registered a drug that is registered in the FDA or EMA and is marketed in a recognized country, it is classified in Group 5.
  • The Ministry instituted a special procedure for this last group in which it relates to the characteristics of bio-similars. (Procedure 127 from April 2014):

Biological formulations are defined as formulations whose active ingredient is derived from a living organism. Due to their complexity and the manufacturing routes, active biological formulations are similar, but not identical. A bio-similar formulation is a biological medical formulation that includes an active ingredient that is similar to the active ingredient of a reference medicinal product. The biosimilar formulation is expected to be similar to the reference medicinal product in quality, biological activity, safety and efficacy, as demonstrated in comparative tests.

The general rules that apply to generic chemical formulations do not apply to bio-similars.

It is found that bio-similars are similar to the reference medicinal product is not classified as a formulation having a new active ingredient, despite the active ingredient not being identical to that of the reference medicinal product.

structural ifferencesIt transpires from this that when discussing biological formulations, one has to consider them differently when looking at the identicality of the material. On one hand, there will be structural differences in the material (which is not the case with generic chemical molecules), but on the other hand, different materials are considered similar even though they do NOT have the same structure, when comparing bio-similars with reference medical products.

Compliance-Road-Sign-Picture

Thus it appears the techno-formalistic test is insufficient to rule regarding the first registration of proteins. The Commissioner does not consider that accepting an explanation of the law that necessarily sees the registration of the protein as the first registration for a protein having the same name, but a different structure that affects the activity, and which requires a full regulatory path to allow it to be marketed, as being in line with the underlying purpose and rationale of the Law.

The connection between the need to undergo full registration and the right to a patent term extension is built into the Law. The purpose of the Law is to compensate the patentee for the period that he cannot utilize the invention due to long regulatory approval procedures. In this regard, that stated by Dr Meir Noam in his ruling concerning the Patent Term Extension for Patent IL 97219 to Novartis (26 December 2005):

According to the rationale hidden in the sections of the Law that relate to patent term extensions, that run like a scarlet thread through the definition, there is no need to extend a patent where the registration period is regular. This is the case, according to Dr Noam, where a drug registration is requested for a pharmaceutical preparation that includes known active ingredients, whose acidity and toxicity have been previously considered by the Ministry of Health or by corresponding bodies abroad. There is no doubt that all new drugs need new authorizations, and it is possible that the regulatory approval will take time. However, the time for the two types of regulatory approvals are not the same.  For a new drug that includes a new active ingredient, it is necessary to conduct all the tests, but a new drug comprising a number of known active ingredients, that have been individually approved in the past for medicinal use, which have proven themselves for treating humans, the regulatory procedure will typically be shorter, since we are travelling along a previously paved and tested road, so an extension is not justified.

The District Court addressed this issue in the Appeal of the Novartis ruling (1063/06 Novartis AG vs. Commissioner of Patents and Trademarks 26 February 2007):

Nevertheless,  even if we ignore the comparative law part of the decision, I think the Commissioner of Patents correctly addressed the rationale of the legislation, as he found it expressed explicitly in the Law, particularly with regard to the differences in pendency for a new drug formulation undergoing registration for the first time, and the time required for registration for a drug comprising materials that have been previously registered as in the case before us, which was pending for five months.

The District Court in Jerusalem came to a similar conclusion in 13281-06-12 Neurim Pharmaceuticals (1991) vs. Commissioner of Patents and Trademarks (27 September 2012):

 When considering the purpose behind the third amendment, which reflects, inter alia, the desire of the legislator to give compensation to the developer of a new drug formulation, for the delay in marketing authorization which sometimes takes years after the patent issues, it is necessary to consider the intention of the legislator in a more limited manner when there is a previous registration. In principle, the previous registration blocks the requested patent term extension since the legislator considers that in cases where a different formulation has been registered prior to the pending case, the tests and research that accompanied the development of the earlier drug will help the company developing the second drug, if the second drug is based on the same active ingredient as the first.

However, the linkage is not one-dimensional in the sense that one can consider cases where the registrant will have to undergo the full regulatory approval but will still not receive the compensation in the form of a patent term extension (see for example section 51 of the Lundbeck ruling).

new formulation

In accordance with that written above, in the current circumstances, when considering medical formulations whose active ingredient is a protein, the Commissioner thinks that firstly one should consider if the formulation was considered as being a new formulation by the Ministry of Health. The Commissioner considers that this condition is a precondition to obtaining a patent term extension under the rationale of the Law, which is to grant patent term extensions to patentees preventing from selling their product due to the need to obtain regulatory approval.

glycosylation

Secondly, one should consider if there are structural differences between the active ingredient of the formulation under consideration and that of previously registered active ingredients.  The differences could be in a number of parameters – the primary structure, secondary and tertiary structural differences, of differences that the protein undergoes on translation, such as glycosylation. Changes in each and every one of these parameters may or may not influence the activity of the material.

With regards to active chemical ingredients, one can claim that the legislator defined enantiomers that, although not structurally identical, can be considered as being the same active ingredient, since the experiments on the active ingredient will shorten the way or help develop drugs based on the same active ingredient. So different salts of the same active ingredient are defined as being the same active ingredient with respect to Section 64D(3) of the Law (it is noted that in other jurisdictions, a different conclusion was reached).

One option is that all biological materials having a different structure, no matter how minor the difference, from another material that was previously registered, will be entitled to a patent term extension. The Commissioner does not adopt this position. Whilst it is accepted that different biological materials can be considered as being similar materials despite the differences, and consequently to benefit from leniencies in obtaining regulatory approval (as in the case of bio-similars), it is difficult to rule that they should be considered as being different materials for purpose of Section 64D(3) of the Law and eligible for patent term extension.

Thus, it is logical that active ingredients that are authorized as bio-similars will not be eligible for patent term extensions. Applying for regulatory approval as a bio-similar is essentially a declaration of the Applicant, that he considers that despite the structural differences, the active ingredient is similar to identical to that registered in the pharmaceutical registry, and thus it is illegible for a patent term extension.

True, the evaluation of bio-similars is longer than that for generic [chemical] materials. Nevertheless, and as clarified in the case-law cited, not all regulatory approval justifies a patent term extension, but only the full regulatory procedure.

In accordance with this, and since there is no structural difference that justifies giving a patent term extension, the Applicant for a patent term extension has to point to parameters relating to the activity of the protein that are related to the structural differences. This test is particularly relevant in places where there is a prima facie strong similarity between the materials, and the structural differences are minor. A difference in activity can testify that the structural difference, though minor, affects the efficacy, and in such cases it may be appropriate to consider the material as being a “new material” as far as patent term extensions are concerned.

Whether a material fulfills the criteria provided hereinabove will be considered on the basis of statements by the Applicant, supporting evidence submitted (for whether the formulation was examined as a new material or not, does not appear in the Registration certificate submitted as part of the request for the patent term extension).

It is clear that due to the scientific complexity of the material, and the current legal basis, the principles given above cannot be formulated as a strict test, and it is likely that further tests will be required for cases having different characteristics.

It is likely that in future, with the accumulation of more scientific knowledge, more advanced analytic procedures will be developed that will enable the behaviour of biological materials to be predicted in a manner analogous to chemical materials today, and  then it will be possible to define structures that can be considered as bio-equivalents.

Comparative Foreign Law

With respect to the clauses relating to patent term extensions, it has been determined that the Law is different in different regimes and so care should be taken when drawing conclusions from foreign law. With this, the definition of Section 64D(3) of the Law which we are attempting to construe, is based on the US Law, and so when considering an issue for the first time, it would be wrong to ignore how other jurisdictions regard the question.

The US Patent Law USC 35 156(a)(5)(B) specifically defines that when discussing a patent that claims a manufacturing technique using recombinative DMA, only the product manufactured by the same process claimed I patent will be considered as a new registration.

 ….

(B) in the case of a patent which claims a method of manufacturing the product which primarily uses recombinant DNA technology in the manufacture of the product, the permission for the commercial marketing or use of the product after such regulatory review period is the first permitted commercial marketing or use of a product manufactured under the process claimed in the patent;

It is not superfluous to note that in Israel there is no comparable law to this Section of the US Law. The Commissioner is not sure that this is a negative arrangement (under which this lack of such a law indicates that it does not apply), but there is certainly a lack of a positive law that states that with respect to proteins fabricated by recombinative DNA, only a protein produced by the patented process can serve as a first registration as far as Section 64D(3) of the Law, rather the question will be tested with respect to the protein as described above.

In the ruling of the UKPTO concerning Ichan School of Medicine, a patent term extension for agalsidase-beta, an enzyme that helps break down glicolophids in the body was considered.

This enzyme is a biological material that has undergone glycosylation in the CHO cell. In that instance, a patent term extension had already been granted for another patent for the same enzyme manufactured endogenously. See O/552/14 SPC/GB13/069 Icahn School of Medicine at Mount Sinai (19 December 2014). In that decision, the adjudicator ruled, inter alia, regarding the identity of the materials. It is noted that the comparison of the materials was not the main issue of the ruling:

At my request, I was also addressed during the hearing on the differences between agalsidase-beta (α-Galactosidase A produced in CHO cells) and agalsidase alpha (α-Galactosidase A produced in human cells). Based on the technical background, which I have summarised above, I am content that these active ingredients are different products for the purposes of the SPC Regulation because of the differing characteristic glycosylation profiles on the enzyme when it is produced in the different cell types. I am therefore of the opinion that each product can be the subject of a separate SPC, and that the requirements of Article 3(c) are satisfied.”

It is not superfluous to note that in the ruling (paragraph 16-17) the Adjudicator noted the connection between the difference in the glycosylation and the activity of the protein.

“16. The mannose-6-phosphate on the α-Galactosidase A is important for targeting the enzyme to the right location within the cell to allow the enzyme to carry out its function of breaking down glycolipids. Mannose-6-phosphate receptors on cells bind to the mannose-6-phosphate on the α-Galactosidase A enzyme to cause the enzyme to be taken up into the cell, and to cause it to be transported to the correct location in the cell. However, the particular position of the mannose-6-phosphate in the sugar chains attached to α-Galactosidase A is not important. It is the overall level of the mannose-6-phosphate on the α-Galactosidase A which is the key factor for controlling the uptake of the enzyme.

  1. Sialic acid on the α-Galactosidase A affects the bioavailability of the enzyme by controlling clearance of the enzyme by the liver. Sialic acid prevents the α-Galactosidase A enzyme from being taken up and removed by the liver.”

Rulings from Holland and Norway (ECLI:NL:RVS:2009:BJ5541) referred to by the Applicant did indeed support the contention that there is a significant difference between biological and chemical materials. Nevertheless, from the machine translation provided by the Applicant (section 2.5.4) it appears that the relevant patent there shows a different antibody activity against TNF-ALPHA which was the subject of that decision, and which had weight in determining that these antibodies are different from the active ingredient there, which is the adalimumab antibody. In regard to the decision by the Norwegian Court of Appeal (15-170539ASD-BORG/01 and 15-204605ASD-BORG/01), here also, it appears that in addition to a structural difference,(that is more significant to that with respect to Factor VIII), there was also a difference in activity, see page 33 of the ruling.

In my opinion, these rulings are compatible with the principles given above, that consider that we are dealing with different materials after a connection between the structure of the protein and its behaviour is determined.

From the general to the specific

Firstly, I note that the request for a patent term extension that the Applicant requested did not hint about the special manufacturing process of the active ingredient of Kovaltry or its different structure. This is the opposite to the request in the US where the material was defined:

(4) Active ingredient Statement

“The active substance in Kovaltry® is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence prepared without human or animal-derived material being added to the cell culture, purification or formulation processes and prepared using a cell line into which the human Factor VIII gene was introduced together with the human heat protein 70 gene. Kovaltry® antihemophilic factor (recombinant) is the first approval of the active ingredient in the product manufactured with the above mentioned manufacturing processes.” 

It appears that among the formulations that the Deputy Chief Examiner cited, Kogenate is the closest to Kovaltry (the active ingredient in the applied for approval and patent term extension). Kogenate, henceforth  rFVIII-FS has the identical sequence of amino acids to that of Kovaltry henceforth BAY 81-8973. So it is necessary to consider if the differences that the Applicant has indicated are sufficient for this to be considered as being an active ingredient not yet registered in the pharmaceutical register.

Appendix 7 of the Applicant’s request for a Hearing is a paper from Garger that the Applicant relied on when noting the differences between the active ingredients and formulations. The Abstract of the paper explains that BAY 81-8973 is manufactured in a manufacturing process that includes inserting the HSP70 gene into cell line used for fabricating the protein Garger S. et al. BAY 81-8973, A Full-Length Recombinant Factor VIII: Manufacturing Processes and Product Characteristics, Hemophilia: 23(2): e67-e78 (2017) henceforth “Garger”:

“BAY 81-8973 (Kovaltry® , Bayer, Berkeley, CA, USA) is an unmodified, full-length recombinant human factor VIII (FVIII) approved for prophylaxis and on-demand treatment of bleeding episodes in patients with haemophilia A. The BAY 81-8973 manufacturing process is based on the process used for sucrose-formulated recombinant FVIII (rFVIII-FS), with changes and enhancements made to improve production efficiency, further augment pathogen safety, and eliminate animal- and human-derived raw materials from the production processes. The baby hamster kidney cell line used for BAY 81-8973 was developed by introducing the gene for human heat shock protein 70 into the rFVIII-FS cell line, a change that improved cell line robustness and productivity. Pathogen safety was enhanced by including a 20-nm filtration step, which can remove viruses, transmissible spongiform encephalopathy agents and potential protein aggregates. No human- or animal-derived proteins are added to the cell culture process, purification or final formulation. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of sialylation of N-linked glycans on the molecular surface. The innovative manufacturing techniques used for BAY 81-8973 yield an effective rFVIII product with a favourable safety profile for treatment of haemophilia A.”

Table 1 of the paper compares the two active ingredients:

124123 table

The table shows that the sequence of amino acids of the proteins is the same, and in both cases it is full length, unmodified human FVIII. The structural differences, as shown in the table and the other appendices, is in the glycosilation, the sialylation and the alpha –gal connectivity of the glycans.

In the Commissioner’s opinion, despite the Applicant showing some structural differences, he did not manage to show that these differences were significant. As ruled above, these materials have many structural similarities and so the issue is whether the structural differences affect the activity of the material.

Referring back to Garger’s paper, the structural difference between the materials expresses itself in the glycosylation and the sialylation. Additionally, according to the paper, there is no certainty that these differences affect the activity of the formulation. On page 71e of the paper it is stated that:

“The manufacturing process used for BAY 81-8973 results in an rFVIII product of enhanced purity with a consistently high degree of sialylation of N-linked glycans on the molecular surface, a posttranslational modification step that is important to the half-life of some mammalian proteins [5, 18, 19]”.

The claim made in the paper is a general one – there are proteins that have glycosylation and sialylation that are important to their half-life, but the paper does not show a preference for rFVIII-FS.

On page 74e it is stated that:

“In clinical trials, the pharmacokinetic profile of BAY 81-8973 was non-inferior to that of rFVIII-FS, and for some variables, BAY 81-8973 showed more favourable pharmacokinetics [18]. Compared with rFVIII-FS, BAY 81-8973 had a longer half-life, higher area underthe curve, longer mean residence time and slower clearance [18]”.

Thus the paper shows that BAY 81-8973 is not inferior to rFVIII-FS and there is no significant difference in the pharma-kokinetic profile. Indeed, the section cited does discuss the preferential half-life but, as is clear from the section quoted above, the paper is not unequivocal.

On page 77 it is stated that Garger:

“The post translational modification sites and structures are confirmed, and high level of sialylation of the branched N-glycans have been shown. This profile could potentially translate to benefits for the patient.”

In this section it is also stated that the gain is a hypothetical suggestion that could be the case for patients treated with the altered molecule, but this is not certain, or even likely.

It is also noted that from the papers cited by the Applicant themselves it is clear that not all changes in glycosylation imply that full regulatory approval procedures are required and there are formulations with different glycosilation profiles that are considered as being bio-similars.

In the marginal note 7 of the Summary of Claims prior to the hearing, the Applicant referred to a paper titled “Biologicals and biosimilars: a review of the science and its implications” Generics and Biosimilars Initiative Journal, Volume 1, 2012, Issue 1, pg. 13.

This paper explains (page 14) that where there are differences between the source formulation and the bio-similar, it is necessary to explain the effect of the differences on the efficacy and tolerance of the drug:

“However, the CHMP requires that any difference in the quality attributes between the biosimilar and its reference product, such as variability in post-translational modifications or differences in impurity profiles should be justified in relation to its potential impact on efficacy and tolerability. The existence of differences in quality attributes between a biosimilar and the reference product is reported in the public assessment reports (EPAR) (visit http://www.ema.europa.eu) made available upon approval of the biosimilar”.

The paper continues and brings examples of bio-similar formulations that are different from the original formulation in their glycosylation profiles.

“For example, for a biosimilar of epoetin alfa, differences are reported with respect to glycosylation (higher levels of phosphorylated high-mannose-type structures, lower levels of N-glycolylneuraminic acid and diacetylated neuramic acids) and oxidation (lower levels of the oxidised variant). For a biosimilar of somatropin, differences in impurities are reported as well as a higher level of deamidated variants.”

In summary, even if we accept that there are certain structural differences between the active ingredients, and even if there are some differences in the parameters relating to the phamarcokinetics and the half-life of the two materials, the Applicant did not manage to establish that the differences are significant, and so the Commissioner concludes that the registration of the active ingredient of Kovaltry is NOT the first registration in the sense of Section 64D(3) of the Law.

The Commissioner is awake to the fact that patent term extensions were issued in the US and some of European countries. However, and as mentioned earlier, in the US there is a specific Section that relates to active ingredients fabricated by recombinative processes. Without a similar Section in the [Israeli] Law, the structure has to be considered in the way discussed above, and consideration of the manufacturing process is not enough.  As to the patent term extensions in Europe, apart from the fact that the mere actuality of an extension in Europe is not in itself justification to allow a patent term extension in Israel, it was not clarified if similar objections to those raised above were raised in Europe and what the answers were, etc.

Before concluding, the Commissioner notes that the Deputy Chief Examiner did not doubt that the conditions of Section 64D(1) are fulfilled:

(1) the material, the process for production or the use thereof, the medical preparation that incorporates the material or the process for production thereof, or the medical equipment claimed in the basic patent and the basic patent remains in effect;

The Applicant’s main claim focused on the active ingredient having a different glycosylation profile, as a result of the introduction of the Heat Shock Protein 70 (HSP70) on the production process as given in the above referenced papers and as noted in the request for a Patent Term Extension in the US.

Nevertheless, the patent for which a Patent Term Extension is requested relates to a manufacturing process that does not mention HSP70. Even if the patent protects the active ingredient BAY 81-8973, in the sense that the active ingredient does not include materials derived from living organisms, in fact, there is no guarantee that the described process will yield a protein having the properties of the active ingredient BAY 81-8973 since the process claimed in the patent, does not require using HSP70.

Thus one can at least raise a doubt that the process for manufacturing the active ingredient in question is claimed in the [so-called] basic patent. Anyway, there is no need to relate to this question at present, since we have concluded that Kogenate is the first registration of Kovaltry.

In addition, and beyond that necessary, the final issue is addressed. The date on which the patent to be extended is requested is 16 April 2018.

Sections 64O(2) states:

(b) The Commissioner will complete the review of the application 11) 2014 for grant of extension within 60 days from the date to begin the review, subject to section 64E(a) or from the date in which the applicant submitted the missing information or rectified the relevant errors, as said under subsection (a1), whichever is latest. (amendment no. 11) 2014

….

(d) Without derogation from the provisions of section 64E(e), and notwithstanding section 64D(1), the Commissioner shall complete the review of the application as said in subsection (b); if an opposition was submitted, he shall make a decision subject to subsection (c), insofar as possible, no later than the end of the term of the basic patent, and for that purpose he may shorten any time prescribed in or under this article.

This ruling issues on the final date of the basic patent. However, the Commissioner feels that Section 64O(4) of the Law acknowledges that there are specific cases where one cannot complete the consideration of a request for a Patent Term Extension before the patent lapses, and in such cases, the consideration can be completed even after the patent lapses. See Section 64E(5)(3) of the Law.

In light of the above, the Commissioner rejects the request for a Patent Term Extension but thanks the Applicant for their detailed and weighty claims in this never discussed issue.

Request for a Patent Term Extension for IL 124123 to Bayer (Biosimilars) ruling by Ofer Alon, 16 April 2018.

COMMENT

I think this ruling is correct, if long-winded. However, apparently, the protein in question obtained regulatory approval very close to the patent lapsing and so, without a patent term extension, the patentee has disclosed his invention without obtaining a monopoly in return. This seems inequitable.

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