Details for Patent: 8,192,719

Which drugs does patent 8,192,719 protect, and when does it expire?

Patent 8,192,719 protects MACRILEN and is included in one NDA.

Protection for MACRILEN has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has eleven patent family members in ten countries.

Summary for Patent: 8,192,719

Title:	Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds
Abstract:	A method of assessing growth hormone deficiency in a human or animal subject, the method comprising administering orally to the subject EP 1572 (Formula I) or EP 1573 (Formula II), obtaining a post-administration sample from the subject, determining the level of growth hormone in the sample and assessing whether the level of growth hormone in the sample is indicative of growth hormone deficiency in the subject. Preferably, the GH level in the sample is measured by immunoassay. Also disclosed is a kit of parts constituting a diagnostic kit comprising: (a) EP 1572 or EP 1573 formulated for oral administration; and (b) means for determining the level of growth hormone in a sample.
Inventor(s):	Finn Larsen
Assignee:	Aeterna Zentaris GmbH
Application Number:	US12/279,805
Patent Claim Types: see list of patent claims	Use; Device; Dosage form;

United States Patent 8,192,719: Scope, Claims, Expiration, and Macimorelin Patent Landscape

US Patent No. 8,192,719 protects diagnostic use of the oral growth hormone secretagogues EP 1572 and EP 1573 to assess growth hormone deficiency. The patent covers administration, timed blood sampling, growth hormone measurement, comparison against control levels, peak-growth-hormone assessment, and diagnostic kits containing the secretagogue and an assay component. The principal commercial relevance is macimorelin, also known as EP 1572 and marketed in the United States as Macrilen.

The patent is a method-of-diagnosis and diagnostic-kit patent, not a broad composition-of-matter patent. Its commercial scope depends on the accused party using the specified secretagogue-based stimulation test, rather than merely selling a growth hormone assay or treating growth hormone deficiency.

What drug and technology does US Patent 8,192,719 cover?

US 8,192,719 covers the use of EP 1572 or EP 1573 as an oral stimulus for measuring growth hormone release.

EP 1572 is associated with macimorelin, a synthetic growth hormone-releasing peptide receptor agonist. Macimorelin stimulates growth hormone secretion through the growth hormone secretagogue receptor and is used diagnostically rather than as chronic hormone-replacement therapy. The FDA approved Macrilen for the diagnosis of adult growth hormone deficiency in December 2017.[1]

The patent claims a diagnostic workflow with these essential elements:

1. Orally administer EP 1572 or EP 1573.
2. Obtain one or more samples after administration.
3. Measure growth hormone in the sample.
4. Compare the measured level with a reference level from a subject known not to have growth hormone deficiency and/or a subject known to have the deficiency.
5. Assess whether the result indicates growth hormone deficiency.

The patent also covers a kit containing:

• EP 1572 or EP 1573 formulated for oral administration; and
• A means for determining growth hormone levels in a sample.

The kit may include diagnostic instructions.

What are the independent claims of US 8,192,719?

The patent has three principal independent claim concepts.

Claim	Independent subject matter	Core requirement
1	Administered diagnostic method	Oral administration of EP 1572 or EP 1573 followed by sampling, growth hormone measurement and comparison
7	Sample-provision diagnostic method	Testing a sample obtained from a subject previously administered EP 1572 or EP 1573
18	Diagnostic kit	Oral EP 1572 or EP 1573 formulation plus means for measuring growth hormone

Claims 1 and 7 are method claims with overlapping technical subject matter but different actors and procedural framing.

Claim 1 requires the actor to administer the secretagogue and conduct or direct the diagnostic assessment. Claim 7 begins with a sample from a subject who has already received the oral secretagogue. That wording is relevant to infringement analysis because it may reach laboratories or diagnostic providers that do not themselves administer the drug.

Claim 18 is directed to a kit of parts. It does not require that the kit actually be used for a diagnosis to fall within the literal wording of the claim, although enforcement would depend on the facts, including commercial purpose, product configuration and applicable indirect-infringement theories.

How do claims 1 through 6 define the diagnostic method?

Claims 1 through 6 form the primary method-of-use group.

Claim 1: Basic oral stimulation test

Claim 1 requires:

• a human or animal subject;
• oral administration of EP 1572 or EP 1573;
• at least one post-administration sample;
• determination of growth hormone level; and
• comparison with a reference sample from a subject known to be normal and/or growth-hormone deficient.

The claim does not require a particular assay platform, a particular threshold, a specific patient age, or a specific sample type. Those limitations appear in dependent claims.

The reference comparison is important. A process that administers macimorelin and merely reports a numerical growth hormone value could raise a claim-construction issue if no comparison to an appropriate reference is performed. In practice, a diagnostic protocol normally includes an interpretive threshold or reference standard, making this limitation commercially significant.

Claims 2 and 3: Pre-dose and post-dose sampling

Claim 2 adds a pre-administration sample. The pre-dose sample can establish a baseline growth hormone level.

Claim 3 requires one or more post-administration samples collected after a suitable interval. The claim does not impose a single mandatory post-dose time point.

Claims 4 and 5: Sampling schedule

Claim 4 specifies intervals of 15 to 30 minutes between samples.

Claim 5 identifies a more detailed schedule:

• minus 30 or minus 15 minutes;
• zero minutes;
• 15 minutes;
• 30 minutes;
• 60 minutes;
• 90 minutes; and
• 120 minutes,

relative to oral administration.

A diagnostic protocol using fewer samples or a different schedule may avoid literal infringement of claim 5, but it could still fall within broader claims 1 or 3 if all other limitations are met.

Claim 6: Peak growth hormone value

Claim 6 covers using the peak level of growth hormone released during the testing period to indicate growth hormone deficiency.

This limitation is commercially relevant because macimorelin testing typically relies on the maximum stimulated growth hormone concentration rather than on a single baseline measurement. A protocol that uses area-under-the-curve analysis, a later time point, or another biomarker may present a different infringement analysis.

How do claims 7 through 17 differ from claims 1 through 6?

Claims 7 through 17 create a second method group focused on testing a previously collected sample.

Claim 7 does not expressly require the testing party to administer EP 1572 or EP 1573. It requires that the sample come from a subject who was orally administered one of those compounds. The claim then requires growth hormone measurement and comparison with a reference level.

This structure may be intended to cover the laboratory or diagnostic-service portion of the workflow. It creates potential divided-infringement issues because administration, sample collection, laboratory testing and clinical interpretation may be performed by different entities.

The dependent claims add the following limitations:

Claim	Limitation
8	Pre-administration sample
9	One or more post-administration samples
10	Sampling at 15- to 30-minute intervals
11	Detailed schedule extending from -30 or -15 minutes through 120 minutes
12	Peak growth hormone assessment
13	Child or adult subject
14	Horse, cow, sheep, pig, goat, cat or dog
15	EP 1572 or EP 1573 dose of 18 to 75 mg
16	Blood, serum or plasma sample
17	Immunoassay measurement

Claims 13 and 14 materially expand the express subject scope beyond adult human diagnosis. The FDA-approved indication is adult human growth hormone deficiency, but the patent claims expressly include children and several animal species.

What do claims 21 through 25 add?

Claims 21 through 25 repeat the principal dependent limitations for claim 1 rather than claim 7.

Claim	Limitation
21	Child or adult human subject
22	Specified animal species
23	18- to 75-mg dose
24	Blood, serum or plasma sample
25	Immunoassay

This claim structure gives the patent parallel dependent-claim coverage for both the administered diagnostic method and the sample-testing method.

The duplication does not create a separate inventive concept. It provides alternative claim paths if a court construes the independent claims differently or finds one claim group inapplicable to a particular party.

What formulations and dosing practices are protected?

The claims do not require a particular excipient system, tablet design, capsule, liquid formulation or packaging configuration. The formulation limitation appears in claim 18, which requires EP 1572 or EP 1573 to be formulated for oral administration.

Claim 15 and claim 23 cover an administered amount between 18 mg and 75 mg. The range is broad relative to a commercial diagnostic dose. A product administered outside that range could avoid those dependent claims while remaining potentially relevant to claims 1 or 7.

The strongest formulation-related protection is therefore functional:

• the product must contain EP 1572 or EP 1573;
• it must be suitable for oral administration; and
• the kit must include a means for determining growth hormone.

The patent does not, based on the supplied claims, claim a particular macimorelin salt, crystal form, impurity profile, manufacturing process, excipient combination or stability profile.

What is the scope of the immunoassay claims?

Claims 17, 20 and 25 expressly identify immunoassay testing.

The independent method claims are broader because they require determining the growth hormone level but do not restrict the measurement technology. Potentially relevant measurement methods could include:

• immunoassays;
• chemiluminescent assays;
• enzyme-linked immunosorbent assays;
• electrochemiluminescence assays; and
• other validated analytical methods.

An immunoassay-specific protocol is more directly aligned with claims 17, 20 and 25. A non-immunoassay protocol could remain within the independent claims if it performs the required growth hormone determination and comparison.

The claims also specify blood, serum or plasma in claims 16 and 24. A saliva, urine or other matrix-based assay would not satisfy those dependent claims literally, although the broader independent claims do not expressly limit the sample matrix.

What is the patent term and expiration date?

US 8,192,719 was issued on June 5, 2012.[2] The patent has a standard 20-year term measured from the relevant nonprovisional priority framework, subject to patent-term adjustment, terminal disclaimers and any applicable patent-term extension.

Public drug-patent listings have associated US 8,192,719 with an expiration date in December 2025. The precise operative date should be taken from the current USPTO patent record and the FDA Orange Book patent listing because patent-term adjustment can change the nominal calculation.[3][4]

The relevant exclusivity milestones are:

Event	Date or period
US 8,192,719 issued	June 5, 2012
Macrilen FDA approval	December 20, 2017
Orphan-drug exclusivity	Generally seven years from approval, subject to statutory exceptions
Listed patent expiry	December 2025, based on public drug-patent listings
Possible commercial transition	After patent expiry and regulatory exclusivity expiry, subject to product-specific entry requirements

Patent expiry and FDA exclusivity are separate. Expiration of US 8,192,719 would not by itself eliminate any remaining regulatory exclusivity, and expiration of orphan-drug exclusivity would not invalidate an unexpired patent.

What is the Orange Book status of Macrilen and US 8,192,719?

Macrilen is an FDA-approved prescription drug identified by the active ingredient macimorelin acetate. The FDA-approved indication is diagnosis of adult growth hormone deficiency.[1]

US 8,192,719 has been associated with the Macrilen patent listing in the FDA Orange Book. The listing is important because an ANDA applicant relying on the Macrilen reference product may need to address the listed patent through a certification under 21 U.S.C. § 355(j)(2)(A)(vii), including a Paragraph IV certification if the applicant asserts that the patent is invalid, unenforceable or will not be infringed.[4][5]

The Orange Book listing does not prove that every claim of the patent covers every macimorelin product. It identifies a patent asserted by the NDA holder or applicant as relevant to the approved drug.

The patent is also unusual from an ANDA perspective because the claims concern a diagnostic method. A generic applicant may seek to limit its labeling, product instructions or distribution practices to avoid inducing performance of the patented diagnostic method. The practical outcome would depend on the final proposed labeling, the reference-product indication and the applicant's proposed use.

Are there Paragraph IV challenges or patent litigation affecting Macrilen?

The main litigation risk would arise from an ANDA applicant filing a Paragraph IV certification against the listed patent. Such a filing could trigger a 30-month stay if the NDA holder or patent owner files an infringement action within the statutory period.[5]

The supplied claim set does not identify a Paragraph IV filing, ANDA number or litigation docket. A definitive current statement regarding an active challenge cannot be derived from the claims alone.

For diligence purposes, the relevant litigation questions are:

• whether an ANDA has been filed for macimorelin;
• whether US 8,192,719 remains listed in the current Orange Book;
• whether a Paragraph IV notice was served;
• whether an action was filed under the Hatch-Waxman statute;
• whether a 30-month stay was triggered;
• whether the parties executed a settlement; and
• whether the settlement permits an agreed launch date before patent expiry.

A product-specific court docket, FDA Orange Book update or ANDA notice would control over historical patent databases.

How strong is the patent estate for macimorelin?

US 8,192,719 is strongest against a commercial diagnostic protocol that closely follows the Macrilen label:

• oral macimorelin administration;
• serial blood sampling;
• growth hormone immunoassay;
• comparison with a diagnostic threshold or reference;
• peak stimulated growth hormone interpretation; and
• use of the test in the claimed dose range.

Its strength is lower against products or services that use:

• a different growth hormone secretagogue;
• a nonoral administration route;
• a different diagnostic biomarker;
• no comparison or diagnostic interpretation;
• a different sample matrix;
• a materially different testing schedule; or
• a different clinical use outside growth hormone deficiency assessment.

The patent does not appear, from the supplied claims, to block all growth hormone deficiency tests. It blocks a defined secretagogue-stimulation approach.

Patent-strength assessment

Factor	Assessment
Claim breadth	Moderate; independent claims cover the core workflow, but require EP 1572 or EP 1573
Composition protection	Limited or absent in the supplied claims
Diagnostic method coverage	Strong for macimorelin-based stimulation testing
Formulation protection	Narrow; primarily limited to oral formulation in the kit claim
Assay coverage	Broad in independent claims, immunoassay-specific in dependent claims
Geographic coverage	US only for this patent
Design-around potential	Moderate, depending on alternative secretagogue, protocol or diagnostic method
Generic exposure	Dependent on ANDA strategy and method-of-use labeling
Manufacturing barrier	Limited from these claims; no process claims are provided

Which companies are relevant to the macimorelin competitive landscape?

Macimorelin originated from the EP1572 development program associated with Aeterna Zentaris and related entities. Commercial rights and ownership interests have changed over time through licensing and corporate transactions. Novo Nordisk has been associated with Macrilen commercialization and the US reference product.[1][6]

The competitive landscape includes:

1. Macrilen or macimorelin-based diagnostic testing.
2. Traditional growth hormone stimulation tests using agents such as insulin, arginine, glucagon or clonidine.
3. Laboratory-developed stimulation protocols.
4. Future small-molecule or peptide growth hormone secretagogues.
5. Potential generic or authorized-generic macimorelin products.

Macrilen's commercial position depends on clinical convenience, safety, test reproducibility, reimbursement, availability and physician acceptance. Its principal differentiation is oral stimulation rather than intravenous insulin tolerance testing or other established stimulation methods.

What generic launch risks exist after patent expiry?

A post-expiry generic launch would face several regulatory and commercial issues.

FDA approval pathway

A macimorelin generic would likely require an ANDA if the applicant can establish pharmaceutical equivalence and bioequivalence to the reference product. The applicant would need to address the active ingredient, dosage form, strength, route of administration, labeling and quality attributes.[5]

Macimorelin is used diagnostically, so clinical equivalence may require careful treatment of the pharmacodynamic response and diagnostic performance. The FDA may evaluate whether conventional bioequivalence methods adequately demonstrate equivalence for a product whose commercial effect is an induced growth hormone response.

Method-of-use exposure

The patent claims create risk even if the generic product itself is chemically identical to the reference product. A generic applicant could face inducement allegations if its labeling encourages the claimed oral stimulation test during the patent term.

Potential risk-reduction strategies could include:

• a section viii statement carving out a patented use, where legally available;
• labeling that omits the patented indication or protocol;
• a Paragraph IV invalidity or noninfringement position;
• a launch after the patent's enforceable expiry; or
• a settlement with an agreed entry date.

The actual feasibility of a carve-out depends on whether the patented diagnostic use is the central or sole approved use.

Are biosimilar risks relevant to US 8,192,719?

No conventional biosimilar pathway applies to macimorelin because macimorelin is a synthetic small-molecule or peptide drug rather than a biologic licensed under the Public Health Service Act.

The relevant competitor category is generic, not biosimilar. A 351(k) biosimilar applicant would not be the normal pathway for a macimorelin product. Competition would instead arise through an ANDA, an authorized generic, a 505(b)(2) application, or a different diagnostic technology.

What manufacturing and intellectual-property barriers remain?

The supplied claims impose little direct manufacturing restriction. They do not claim:

• a specific synthetic route;
• a starting-material selection;
• a purification sequence;
• a solid-state form;
• a polymorph;
• a salt;
• a formulation excipient;
• a container-closure system; or
• a manufacturing control method.

Manufacturing barriers may still arise from other patents, trade secrets, regulatory specifications, supplier qualification and analytical-method validation. Those barriers cannot be attributed to US 8,192,719 without identifying additional patent families.

The patent's principal barrier is use-based. A competitor that can manufacture macimorelin but sells it for the same patented diagnostic workflow may face greater exposure than a competitor that develops an alternative growth hormone deficiency test.

How does US 8,192,719 compare with alternative growth hormone deficiency tests?

Test approach	Oral secretagogue required	Covered by supplied claims?	Principal issue
Macimorelin stimulation test	Yes	Yes, if EP 1572 or EP 1573 is used	Core patent scope
Insulin tolerance test	No	No	Different stimulant and protocol
Arginine stimulation test	No	No	Different stimulant
Glucagon stimulation test	No	No	Different stimulant
Clonidine stimulation test	No	No	Different pharmacologic mechanism
Baseline growth hormone measurement	No	Generally no	Lacks claimed oral administration
Alternative biomarker test	No	No, absent claimed steps	Different diagnostic basis

The patent does not prevent competitors from offering non-macimorelin growth hormone stimulation tests. It is a product-specific diagnostic-use patent.

Key Takeaways

• US 8,192,719 covers diagnostic assessment of growth hormone deficiency using orally administered EP 1572 or EP 1573.
• EP 1572 is associated with macimorelin, the active ingredient in Macrilen.
• Claims 1 and 7 are the main method claims; claim 18 covers a diagnostic kit.
• The patent covers administration, sampling, growth hormone measurement, reference comparison and diagnostic interpretation.
• Dependent claims cover serial sampling, peak growth hormone measurement, 18- to 75-mg dosing, blood/serum/plasma samples and immunoassays.
• The patent expressly includes children and several animal species, although the FDA-approved Macrilen indication is adult human growth hormone deficiency.
• Public drug-patent listings associate the patent with a December 2025 expiration date.
• Generic risk centers on method-of-use infringement and ANDA certification strategy, not biosimilar competition.
• The claims do not provide broad composition-of-matter, manufacturing-process or formulation protection.
• Alternative tests using insulin, arginine, glucagon or clonidine are outside the supplied claim scope because they do not use EP 1572 or EP 1573.

FAQs About US Patent 8,192,719 and Macrilen

What is EP 1572 in US Patent 8,192,719?

EP 1572 is the development code associated with macimorelin, an orally administered growth hormone secretagogue used to stimulate growth hormone release during diagnostic testing.

Does US 8,192,719 cover macimorelin as a chemical compound?

Not based on the supplied claims. The claims cover diagnostic methods and a diagnostic kit containing EP 1572 or EP 1573. They do not recite a standalone chemical composition claim.

Can a laboratory infringe US 8,192,719 without administering macimorelin?

Potentially. Claim 7 is directed to testing a sample from a subject who has already received EP 1572 or EP 1573. The infringement analysis would depend on the laboratory's activities and the claim construction adopted by a court.

Does the patent cover pediatric growth hormone deficiency testing?

Claims 13 and 21 expressly include child subjects. The FDA-approved Macrilen indication identified in the product labeling is diagnosis of adult growth hormone deficiency, so patent scope and FDA labeling scope are different questions.

Is a macimorelin biosimilar expected to challenge this patent?

No. Macimorelin is not ordinarily addressed through the biosimilar pathway. A competing macimorelin product would more likely use an ANDA or 505(b)(2) pathway, subject to applicable patent and regulatory requirements.

References

1. U.S. Food and Drug Administration. (2017). Macrilen (macimorelin acetate) prescribing information. FDA.

2. United States Patent and Trademark Office. (2012). U.S. Patent No. 8,192,719, methods of assessing growth hormone deficiency. USPTO.

3. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. USPTO.

4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.

5. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j).

6. Aeterna Zentaris Inc. (2017). Macimorelin and Macrilen commercial and licensing disclosures. Company filings.

Drugs Protected by US Patent 8,192,719

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Aeterna Zentaris	MACRILEN	macimorelin acetate	FOR SOLUTION;ORAL	205598-001	Dec 20, 2017		DISCN	Yes	No					Y

Foreign Priority and PCT Information for Patent: 8,192,719

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	0603295.7	Feb 18, 2006

PCT Information
PCT Filed	February 19, 2007	PCT Application Number:	PCT/GB2007/000566
PCT Publication Date:	August 23, 2007	PCT Publication Number:	WO2007/093820

International Family Members for US Patent 8,192,719

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Cyprus	1115080
Denmark	1984744
European Patent Office	1984744
Spain	2404582
United Kingdom	0603295