US Patent 9,604,990 Scope, Claims, and US Patent Landscape for Pemetrexed Diacid Crystalline Form 2

US 9,604,990 is a crystalline-polymorph patent focused on a specific solid state of pemetrexed diacid labeled “crystalline Form 2.” The independent claim set is split between (i) product claims defined by powder X-ray diffraction (PXRD) peak sets and purity constraints vs other crystalline forms, and (ii) a specific crystallization process converting pemetrexed disodium to the diacid using water/methanol, controlled pH, precipitation, and drying at 60–90°C. Dependent claims further narrow the Form 2 definition by additional PXRD peak subsets, an anhydrous limitation, and thermal gravimetric weight-loss constraints.

Given only the claim text provided, this analysis maps claim coverage, likely claim construction pressure points, and the competitive implications for generic and salt-polymorph manufacturing routes. A full patent landscape across all related US filings cannot be completed from the provided text alone.

What does US 9,604,990 claim as “crystalline Form 2” of pemetrexed diacid?

Direct answer: It claims a polymorph defined by a PXRD fingerprint plus substantially exclusivity/purity versus other crystalline forms.

Independent product claim structure (Claim 1)

Claim 1 defines the product as:

Crystalline Form 2 of pemetrexed diacid
Characterized by a PXRD powder pattern with peaks at about:
- 9.0, 12.7, 14.4, 16.3, and 25.3 ± 0.2 degrees 2θ
Where Form 2 is substantially free of other crystalline forms of pemetrexed diacid.

What this means for scope:

The patent’s core is a polymorph identification + purity regime.
The claim does not require an exact phase percentage for Claim 1. That comes in later dependent claims (Claims 12–15), which impose numeric impurity thresholds.

Dependent PXRD narrowing (Claims 2–4)

The dependent claims expand/lock in the PXRD signature:

Claim 2 adds peak set around:
- 13.4, 13.8, 17.2, 25.9, and 27.3 ± 0.2
Claim 3 adds another set around:
- 15.5, 18.1, 18.4, 27.9, and 31.6 ± 0.2
Claim 4 allows definition “as substantially depicted in FIG. 2.”

Claim-construction pressure points:

“About” and “substantially depicted” can create interpretive range disputes (measurement conditions, instrument calibration, sample prep).
The independent Claim 1 requires only the initial five peaks; dependent claims increase certainty by adding more peaks and tight +/- tolerances for two peaks.

Thermal stability limitation (Claim 5)

Weight loss not more than 1.5% up to 120°C by TGA

This supports an intended anhydrous or low-volatile behavior consistent with solid-state characterization used to distinguish polymorphs.

Anhydrous requirement (Claim 6)

Explicitly limits Form 2 to an anhydrous form.

This is a major scope limiter: it excludes hydrates/solvates and any Form 2 preparation that retains residual water above the implied tolerance (even if PXRD matches).

How broad are the purity and “other crystalline forms” limitations (Claims 1, 12–15)?

Direct answer: The claim set escalates from qualitative “substantially free” (Claim 1) to hard numeric thresholds (Claims 12–15).

Qualitative purity (Claim 1)

“Substantially free of other crystalline forms.”

This is often litigated because it is not a single number. In practice, this pushes parties to quantify phase content by PXRD Rietveld analysis or similar methods. Enforcement depends on:

whether accused product exhibits Form 2 peaks consistent with the fingerprint, and
whether the measured fraction of other forms exceeds what the patentee will argue is “substantially.”

Quantitative phase impurity thresholds (Claims 12–15)

Claim 12: ≤ 10% of another form
Claim 13: ≤ 5%
Claim 14: ≤ 3%
Claim 15: ≤ 1%

Implications for generic manufacturing:

Any commercial route that generates mixtures of polymorphs may need explicit solid-state control.
If a competitor can show it produces a different polymorph distribution or higher impurity fraction, it may argue it falls outside the numeric-dependent claim scope (though Claim 1 could still be asserted via “substantially free”).

Risk map:

If an accused product’s PXRD fingerprint aligns closely to Form 2 but includes a small fraction of other forms, enforcement may target the lower-threshold dependent claims (Claims 14–15) if phase content is low enough.
If the fraction is high, the patent might still be asserted under Claim 1’s “substantially free,” depending on measurement interpretation.

What is the scope of US 9,604,990’s process claim (Claims 7–11)?

Direct answer: It covers a narrow precipitation crystallization route converting pemetrexed disodium to pemetrexed diacid Form 2 under controlled solvent composition, pH, and drying conditions.

Independent process claim (Claim 7)

A process comprising:

a) Dissolve pemetrexed disodium in water + methanol at 15–30°C to form a solution
b) Adjust pH to 2.5–3.5 with an acid to form a precipitate
c) Isolate the precipitate
d) Dry at 60–90°C to provide crystalline Form 2 of pemetrexed diacid

Process product match (Claim 8)

Adds that the crystalline Form 2 is isolated substantially free of other crystalline forms.

Solvent ratio limitation (Claim 9)

Water:methanol 3:1 to 1:1

This is a meaningful restriction:

routes using substantially higher methanol or lower methanol relative to water would fall outside Claim 9.

Acid limitation (Claims 10–11)

Inorganic acids: HCl, HBr, H2SO4 (Claim 10)
Organic acids: acetic, trifluoroacetic, methanesulfonic, toluenesulfonic and mixtures (Claim 11)

This is a bounded acid list. Alternative acids (e.g., nitric acid, phosphoric acid, citric acid, formic acid) are not enumerated here, which can support design-around if the competitor can still obtain Form 2 through non-listed acids.

What is and is not required

The claim does not specify crystallization time, mixing rate, addition order of acid, or filtration method. Those factors still matter in practice but are not literal claim elements.
It does require drying within 60–90°C. A competitor drying at materially different temperatures may avoid literal infringement of the drying step.

How do the PXRD peak constraints and “FIG. 2” language affect enforcement?

Peak lists with tolerances create both strength and litigation risk

Claim 1 has “about” peaks and a tighter explicit tolerance on 25.3 ± 0.2°
Dependent claims also have explicit tolerances for 27.3 ± 0.2° and 31.6 ± 0.2°

This suggests the patentee selected peaks that are:

reproducible, and
discriminating across polymorphs.

But “about” means the patentee must define workable error bounds. Accused infringers can challenge:

whether the accused spectrum was collected under comparable conditions, and
whether peak shifts or missing peaks result from measurement variability rather than different solid form.

“Substantially depicted in FIG. 2” is a broad locator

It is easier to argue that a spectrum matches “substantially” than to prove exact peak-by-peak reproduction. That increases enforcement leverage but also creates disputes over what “substantially” means relative to the figure and legend.

Is US 9,604,990 limited to anhydrous Form 2, or can hydrates still matter?

Direct answer: Claim 6 is limited to an anhydrous form. Other claims (1–5, 7–8) do not explicitly use the “anhydrous” term.

Practical effect:

If an accused solid matches Form 2 PXRD but is hydrated, it may still fall within product claims 1–5 if the “anhydrous” limitation is only present in claim 6.
Claim 5’s TGA weight loss limit (≤1.5% up to 120°C) can act as an indirect “not hydrated” constraint even without the word “anhydrous.”

How strong is the patent estate for this specific Form 2 family, based on claim design?

Direct answer: The claim design is typical of polymorph enforcement strategy: broad independent product/process anchored to a fingerprint, then dependent narrowing by additional peaks, purity, anhydrous/TGA, and tight process parameters.

Strength drivers in the claims

Specific PXRD peak set with at least two peaks carrying explicit tolerances.
Purity control eliminates claims to trivial impurities.
Process claim ties to a defined synthesis route rather than generic “crystallize at acid pH.”
Solvent ratio and pH window are narrow enough to matter.

Potential weakness vectors

“Substantially free” (Claim 1, Claim 8) is a litigation magnet.
“About” peak angles invite expert disputes.
If competitors can obtain a Form 2-like PXRD but with materially different additional peaks (Claims 2–3) or higher impurity content, they may still try to avoid dependent claims and challenge whether Claim 1 is met.

What does this mean for US generic entry risks for pemetrexed diacid Form 2?

Direct answer: The patent creates a specific infringement pathway for manufacturers who (i) produce Form 2 solids with the claimed PXRD pattern and low impurity of other forms, or (ii) manufacture using the claimed precipitation process (disodium to diacid with the listed solvent/pH/acid/drying conditions).

High-risk manufacturing scenarios

Producing an anhydrous diacid solid whose PXRD matches the Form 2 fingerprint and meets TGA weight loss ≤1.5% up to 120°C.
Converting disodium to diacid by:
- water/methanol at 15–30°C,
- acidification to pH 2.5–3.5 using one of the enumerated acids,
- drying at 60–90°C, and
- achieving low other-form fractions.

Common design-around levers implied by claim elements

Changing solvent system outside 3:1–1:1 water:methanol
Using an acid outside Claims 10–11
Drying outside 60–90°C
Producing a polymorph distribution that fails “substantially free” or numeric thresholds
Producing hydrates/solvates such that TGA and/or “anhydrous” limitations are not satisfied

These are claim-element levers, not guarantees of non-infringement, but they map directly to potential infringement defenses.

When does US 9,604,990 lose exclusivity?

Direct answer: Exclusivity timing cannot be calculated from the information provided because the filing date, patent issue date, and any adjustments (or terminal disclaimers) are not provided.

What is the Orange Book status of US 9,604,990 for pemetrexed diacid?

Direct answer: Orange Book listing status cannot be determined from the information provided because US 9,604,990’s FDA product linkage (application number, listed patents, and Orange Book entries) is not provided.

What patent litigation or Paragraph IV challenges affect this estate?

Direct answer: Litigation status cannot be mapped from the information provided because docket data, parties, and FDA Paragraph IV filings tied to this patent are not included.

Key claim-by-claim coverage matrix (what an accused product/process must do)

Product infringement elements (Claims 1–6)

Claim	Core requirement	Discriminators that narrow scope
1	Crystalline Form 2 of pemetrexed diacid	PXRD peaks at ~9.0, 12.7, 14.4, 16.3, 25.3 ±0.2; “substantially free” of other forms
2	As Claim 1	Adds PXRD peaks ~13.4, 13.8, 17.2, 25.9, 27.3 ±0.2
3	As Claim 2	Adds PXRD peaks ~15.5, 18.1, 18.4, 27.9, 31.6 ±0.2
4	As Claim 1	Spectrum “substantially depicted in FIG. 2”
5	As Claim 1	TGA weight loss ≤1.5% up to 120°C
6	As Claim 1	Explicitly anhydrous Form 2

Purity narrowing (Claims 12–15)

Claim	Other crystalline forms allowed
12	≤10%
13	≤5%
14	≤3%
15	≤1%

Process infringement elements (Claims 7–11)

Claim	Process elements	Narrowing levers
7	Disodium → Form 2 diacid via dissolution, pH adjust, precipitation, drying	Water/methanol 15–30°C; pH 2.5–3.5; drying 60–90°C
8	As Claim 7	Product isolated substantially free of other crystalline forms
9	As Claim 7	Water:methanol ratio 3:1 to 1:1
10	As Claim 7	Acid is HCl, HBr, or H2SO4
11	As Claim 7	Acid is acetic, TFA, methanesulfonic, toluenesulfonic, or mixtures

Key Takeaways

US 9,604,990 is a polymorph and process patent anchored to PXRD-defined crystalline Form 2 of pemetrexed diacid plus phase purity constraints.
Product scope is strongest where PXRD matches Claim 1 and the solid is low in other polymorphs, with dependent claims tightening via additional peaks, TGA ≤1.5% to 120°C, and anhydrous status.
Process scope is tied to a specific precipitation route from pemetrexed disodium using water/methanol (15–30°C; 3:1 to 1:1), pH 2.5–3.5, enumerated acids, and drying at 60–90°C.
Enforcement is likely to hinge on solid-state analytics: PXRD peak matching under comparable conditions and quantification of other crystalline forms content.

FAQs

Can a manufacturer avoid US 9,604,990 by using a different acid to form the pemetrexed diacid?
The process claims enumerate acids (Claims 10–11). Using non-listed acids can create a literal-claim design-around route if Form 2 still forms without moving into the listed acid categories.
Does “substantially free of other crystalline forms” allow minor polymorph impurities to keep products outside the claims?
Claim 1 is qualitative; Claims 12–15 are quantitative. Litigation typically turns on the measured other-form fraction and what the patentee will argue qualifies as “substantially free.”
If PXRD matches only Claim 1’s five peaks, does that still risk infringement?
Yes. Claim 1 requires only the base peak set plus “substantially free” of other forms. Dependent claims add additional peaks but are not required for Claim 1.
Do hydrates of pemetrexed diacid fall outside the patent?
Claim 6 explicitly requires an anhydrous form, and Claim 5 imposes a TGA weight loss cap. Hydrates may still be implicated through Claims 1–4 if their PXRD matches and TGA behavior fits the Claim 5 thresholds where asserted.
Is the process patent easier to design around than the product patent?
The process claim is narrow in solvent ratio, pH window, acid list, and drying temperature. Changing one of these elements can reduce literal risk, but product claims can still be asserted if the final solid is Form 2.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eagle Pharms	PEMFEXY	pemetrexed	SOLUTION;INTRAVENOUS	209472-001	Feb 8, 2020		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial		Y			⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2962383	⤷ Start Trial
Canada	3015436	⤷ Start Trial
European Patent Office	3212193	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,604,990

Which drugs does patent 9,604,990 protect, and when does it expire?

Summary for Patent: 9,604,990